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Supplemental Digital Content is available in the text., Pulsatile blood pressure (BP) confers cardiovascular risk. Whether associations of cardiovascular end points are tighter for central systolic BP (cSBP) than peripheral systolic BP (pSBP) or central pulse pressure (cPP) than peripheral pulse pressure (pPP) is uncertain. Among 5608 participants (54.1% women; mean age, 54.2 years) enrolled in nine studies, median follow-up was 4.1 years. cSBP and cPP, estimated tonometrically from the radial waveform, averaged 123.7 and 42.5 mm Hg, and pSBP and pPP 134.1 and 53.9 mm Hg. The primary composite cardiovascular end point occurred in 255 participants (4.5%). Across fourths of the cPP distribution, rates increased exponentially (4.1, 5.0, 7.3, and 22.0 per 1000 person-years) with comparable estimates for cSBP, pSBP, and pPP. The multivariable-adjusted hazard ratios, expressing the risk per 1-SD increment in BP, were 1.50 (95% CI, 1.33–1.70) for cSBP, 1.36 (95% CI, 1.19–1.54) for cPP, 1.49 (95% CI, 1.33–1.67) for pSBP, and 1.34 (95% CI, 1.19–1.51) for pPP (P

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

Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality.Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality.Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardiovascular mortality, stratified based on eGFR (>90, between 60 and 90 and Conclusions: hyperuricemia is a risk factor for cardiovascular and all-cause mortality additively to eGFR strata and albuminuria, in patients at cardiovascular risk.

Participant-level meta-analyses assessed the age-specific relevance of office blood pressure to cardiovascular complications, but this information is lacking for out-of-office blood pressure. At baseline, daytime ambulatory (n=12 624) or home (n=5297) blood pressure were measured in 17 921 participants (51.3% women; mean age, 54.2 years) from 17 population cohorts. Subsequently, mortality and cardiovascular events were recorded. Using multivariable Cox regression, floating absolute risk was computed across 4 age bands (≤60, 61-70, 71-80, and >80 years). Over 236 491 person-years, 3855 people died and 2942 cardiovascular events occurred. From levels as low as 110/65 mm Hg, risk log-linearly increased with higher out-of-office systolic/diastolic blood pressure. From the youngest to the oldest age group, rates expressed per 1000 person-years increased (P

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 called for innovation in addressing age-related disabilities. Our study aimed to identify and validate a urinary peptidomic profile (UPP) differentiating healthy from unhealthy ageing in the general population, to test the UPP predictor in independent patient cohorts, and to search for targetable molecular pathways underlying age-related chronic diseases. METHODS: In this prospective population study, we used data from participants in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO), done in northern Belgium from 1985 to 2019, and invited participants to a follow-up examination in 2005-10. Participants were eligible if their address was within 15 km of the examination centre and if they had not withdrawn consent in any of the previous examination cycles (1985-2004). All participants (2005-10) were also invited to an additional follow-up examination in 2009-13. Participants who took part in both the 2005-10 follow-up examination and in the additional 2009-13 follow-up visit constituted the derivation dataset, which included their 2005-10 data, and the time-shifted internal validation dataset, which included their 2009-13 data. The remaining participants who only had 2005-10 data constituted the synchronous internal validation dataset. Participants were excluded from analyses if they were incapacitated, had not undergone UPP, or had either missing or outlying (three SDs greater than the mean of all consenting participants) values of body-mass index, plasma glucose, or serum creatinine. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. The multidimensional UPP signature reflecting ageing was generated from the derivation dataset and validated in the time-shifted internal validation dataset and the synchronous validation dataset. It was further validated in patients with diabetes, COVID-19, or chronic kidney disease (CKD). In FLEMENGHO, the mortality endpoints were all-cause, cardiovascular, and non-cardiovascular mortality; other endpoints were fatal or non-fatal cancer and musculoskeletal disorders. Molecular pathway exploration was done using the Reactome and Kyoto Encyclopedia of Genes and Genomes databases. FINDINGS: 778 individuals (395 [51%] women and 383 [49%] men; aged 16·2-82·1 years; mean age 50·9 years [SD 15·8]) from the FLEMENGHO cohort had a follow-up examination between 2005 and 2010, of whom 559 participants had a further follow-up from Oct 28, 2009, to March 19, 2013, and made up the derivation (2005-10) and time-shifted internal validation (2009-13) datasets. 219 were examined once and constituted the synchronous internal validation dataset (2005-10). With correction for multiple testing and multivariable adjustment, chronological age was associated with 210 sequenced peptides mainly showing downregulation of collagen fragments. The trained model relating chronological age to UPP, derived by elastic net regression, included 54 peptides from 17 proteins. The UPP-age prediction model explained 76·3% (r=0·87) of chronological age in the derivation dataset, 54·4% (r=0·74) in the time-shifted validation dataset, and 65·3% (r=0·81) in the synchronous internal validation dataset. Compared with chronological age, the predicted UPP-age was greater in patients with diabetes (chronological age 50·8 years [SE 0·37] vs UPP-age 56·9 years [0·30]), COVID‑19 (53·2 years [1·80] vs 58·5 years [1·67]), or CKD (54·6 years [0·97] vs 62·3 years [0·85]; all p

Background Pulse pressure (PP) reflects the age-related stiffening of the central arteries, but no study addressed the management of the PP-related risk over the human lifespan. Methods In 4,663 young (18–49 years) and 7,185 older adults (≥50 years), brachial PP was recorded over 24 hours. Total mortality and all major cardiovascular events (MACEs) combined were coprimary endpoints. Cardiovascular death, coronary events, and stroke were secondary endpoints. Results In young adults (median follow-up, 14.1 years; mean PP, 45.1 mm Hg), greater PP was not associated with absolute risk; the endpoint rates were ≤2.01 per 1,000 person-years. The adjusted hazard ratios expressed per 10-mm Hg PP increments were less than unity (P ≤ 0.027) for MACE (0.67; 95% confidence interval [CI], 0.47–0.96) and cardiovascular death (0.33; 95% CI, 0.11–0.75). In older adults (median follow-up, 13.1 years; mean PP, 52.7 mm Hg), the endpoint rates, expressing absolute risk, ranged from 22.5 to 45.4 per 1,000 person-years and the adjusted hazard ratios, reflecting relative risk, from 1.09 to 1.54 (P < 0.0001). The PP-related relative risks of death, MACE, and stroke decreased >3-fold from age 55 to 75 years, whereas absolute risk rose by a factor 3. Conclusions From 50 years onwards, the PP-related relative risk decreases, whereas absolute risk increases. From a lifecourse perspective, young adulthood provides a window of opportunity to manage risk factors and prevent target organ damage as forerunner of premature death and MACE. In older adults, treatment should address absolute risk, thereby extending life in years and quality., Graphical Abstract Graphical Abstract

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 Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting combined (fatal and non-fatal) cerebrovascular (CBV) events in the whole database. The URic acid Right for heArt Health study is a nationwide, multicenter, observational cohort study involving data on subjects aged 18-95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 120.7 ± 61.8 months. A total of 14,588 subjects were included in the analysis. A prognostic cut-off value of SUA able to discriminate combined CBV events (>4.79 mg/dL or >284.91 µmol/L) was identified by means of receiver operating characteristic curve in the whole database. Multivariate Cox regression analysis adjusted for confounders (age, sex, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, body mass index, low-density lipoprotein cholesterol, and use of diuretics) identified an independent association between SUA and combined CBV events in the whole database (HR 1.249, 95% confidence interval, 1.041-1.497, p = 0.016). The results of the present study confirm that SUA is an independent risk marker for CBV events after adjusting for potential confounding variables, including arterial hypertension, and demonstrate that >4.79 mg/dL is a valid prognostic cut-off value.

Supplemental Digital Content is available in the text., Major adverse cardiovascular events are closely associated with 24-hour blood pressure (BP). We determined outcome-driven thresholds for 24-hour mean arterial pressure (MAP), a BP index estimated by oscillometric devices. We assessed the association of major adverse cardiovascular events with 24-hour MAP, systolic BP (SBP), and diastolic BP (DBP) in a population-based cohort (n=11 596). Statistics included multivariable Cox regression and the generalized R2 statistic to test model fit. Baseline office and 24-hour MAP averaged 97.4 and 90.4 mm Hg. Over 13.6 years (median), 2034 major adverse cardiovascular events occurred. Twenty-four-hour MAP levels of

Aims Whether the association between uric acid (UA) and cardiovascular disease is influenced by some facilitating factors is unclear. The aim of this study was to investigate whether the risk of cardiovascular mortality (CVM) associated with elevated UA was modulated by the level of resting heart rate (HR). Methods and results Multivariable Cox analyses were made in 19 128 participants from the multicentre Uric acid Right for heArt Health study. During a median follow-up of 11.2 years, there were 1381 cases of CVM. In multivariable Cox models both UA and HR, either considered as continuous or categorical variables were independent predictors of CVM both improving risk discrimination (P ≤ 0.003) and reclassification (P Conclusion This data suggest that the contribution of UA to determining CVM is modulated by the level of HR supporting the hypothesis that activation of the sympathetic nervous system facilitates the action of UA as a cardiovascular risk factor.

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 P

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.

In affluent societies blood pressure increases with age from early life to the eighth decade with sex differences. Before middle age, lower blood pressure values are observed in women than in coeval men, whereas the reverse seems to occur thereafter. Menopause is considered the major determinant of blood pressure rise in women. If this hypothesis is well-founded, menopause can be regarded as one of the main cardiovascular risk factors, involving more than half of the human population, as well as the most ineluctable. In industrialized countries, age at menopause ranges between 50 and 52 years. The popular message is that fertile women are protected from cardiovascular risk by circulating estrogens, a privilege that is lost when postmenopausal women become not different from men from the point of view of risk factors and cardiovascular events. Nevertheless, the hypothesis that menopause or the estrogen decrease are per se associated to blood pressure increase is still under debate. Indeed, the epidemiological challenge is due to the coincidence between advancing menopause and aging, and also to the evidence that both menopause and blood pressure have common determinants such as body mass index, diet, smoking, and socio-economic class. The strongest doubt is whether menopause is a dependent or independent risk factor for high BP, i.e. whether its action on blood pressure-if any-is due directly to estrogen fall or to other indirect factors.

Objective:Serum uric acid (SUA) is a predictor of cardiovascular disease (CVD), but its levels that discriminate risk for CVD and mortality remain unknown. We used a large Italian population comprising >30000 subjects to assess the threshold of SUA that increases the risk of total and CVD mortality.

Objective:Searching for a prognostic cut-off value of serum uric acid (SUA) for ischaemic stroke in a large regional-based Italian cohort of men and women in the frame of the URRAH study (URic Acid Right for heArt Health).Design and method:The large database URRAH collects data from cohorts epidemio

Objective The relationship between body fatness and cognitive pattern at a population level was investigated. Methods Among 500 unselected subjects from the general population, the role of body mass index (BMI) and body fat mass (BFM) on a mini-mental state examination (MMSE) and on a battery of paper and pencil neuropsychological tests was analyzed. Multiple linear regressions, accounting for potential confounders, were used. Results In fully adjusted models, MMSE (coefficient +0.027, 95% confidence intervals, 0.017-0.177), the clock drawing test (+0.141, 0.053-0.226), and the trail making test A (+1.542, 0.478-2.607) were positively associated with BMI. Adding BFM to the models, no associations were observed. The tests were also positively associated with BFM (+0.056, 0.021-0.091; +0.063, 0.025-0.101; +0.592, 0.107-1.077; respectively). At analysis of covariance, the same tests were significantly better performed over 29.4 kg m−2 of BMI. After adding BFM as further confounder, all differences in performance across BMI were no longer significant. The three tests were better performed over 34.6 kg of BFM. Conclusions Higher BMI and particularly higher BFM are positively associated with better performance at the cognitive tasks exploring selective attention and executive functions.

Background The general belief is that caffeine increases the risk of hyperkinetic arrhythmias, including atrial fibrillation. The aim of this study is to investigate the effect of chronic caffeine intake on incident atrial fibrillation in general population. Design and methods A population cohort of 1475 unselected men and women observed for 12 years and left free to intake food or beverages containing caffeine was studied. Subjects were stratified into tertiles of caffeine intake both in the whole cohort and after genotyping for the –163C > A polymorphism of the CYP1A2 gene, regulating caffeine metabolism. Results In the whole cohort, the 12-year incidence of atrial fibrillation was significantly lower in the third (2.2%) than in the first (10.2%) or second (5.7%) tertile of caffeine intake ( P Conclusions A higher caffeine intake (>165 mmol/day or > 320 mg/day) is associated with a lower incidence of atrial fibrillation in the 12-year epidemiological prospective setting based on the general population.

Overweight clusters with high blood pressure (BP), but the independent contribution of both risk factors remains insufficiently documented. In a prospective population study involving 8467 participants (mean age 54.6 years; 47.0% women) randomly recruited from 10 populations, we studied the contribution of body mass index (BMI) to risk over and beyond BP, taking advantage of the superiority of ambulatory over conventional BP. Over 10.6 years (median), 1271 participants (15.0%) died and 1092 (12.9%), 637 (7.5%) and 443 (5.2%) experienced a fatal or nonfatal cardiovascular, cardiac or cerebrovascular event. Adjusted for sex and age, low BMI (20.7 kg m(-2)) predicted death (hazard ratio (HR) vs average risk, 1.52; P0.0001) and high BMI (or = 30.9 kg m(-2)) predicted the cardiovascular end point (HR, 1.27; P=0.006). With adjustments including 24-h systolic BP, these HRs were 1.50 (P0.001) and 0.98 (P=0.91), respectively. Across quartiles of the BMI distribution, 24-h and nighttime systolic BP predicted every end point (1.13or = standardized HRor = 1.67; 0.046or = P0.0001). The interaction between systolic BP and BMI was nonsignificant (Por = .22). Excluding smokers removed the contribution of BMI categories to the prediction of mortality. In conclusion, BMI only adds to BP in risk stratification for mortality but not for cardiovascular outcomes. Smoking probably explains the association between increased mortality and low BMI.

Objective: Previous studies testing the hypothesis that symptoms of anxiety and depression increase blood pressure (BP) levels show inconsistent and limited findings. We examined the association between those symptoms across adult life and BP in late middle age. Methods: Using data from 1683 participants from the MRC NSHD, we investigated associations between affective symptoms at ages 36, 43, 53 and 60–64 years and SBP and DBP at age 60–64. Multivariable linear regression was used to examine the effect on BP of affective symptoms at each age separately and as a categorical cumulative score based on the number of times an individual was classified as a ‘case’. Models were adjusted for sex, BMI, educational attainment, socio-economic position, heart rate, lifestyle factors and antihypertensive treatment. Results: In fully adjusted models, we observed lower SBP in study members with case-level symptoms at one to two time-points [−1.83 mmHg; 95% confidence interval (CI) −3.74 to 0.01] and at three to four time-points (−3.93 mmHg; 95% CI −7.19 to −0.68) compared with those never meeting case criteria suggesting a cumulative inverse impact of affective symptoms on SBP across adulthood (P value for trend 0.022). Sex and BMI had a large impact on the estimates while not other confounders. Potential mediators such as heart rate and lifestyle behaviours had a little impact on the association. SBP at age 36 and behavioural changes across adulthood, as additional covariates, had a little impact on the association. A similar but weaker trend was observed for DBP. Conclusion: A cumulative effect of symptoms of anxiety and depression across adulthood results in lower SBP in late middle age that is not explained by lifestyle factors and antihypertensive treatment. Mechanisms by which mood may impact BP should be investigated.

Age- sex- and ethnicity-specific prediction of cardiovascular outcomes by in-office and out-of-the-office blood pressure : a subject-level meta-analysis of 17,383 adults enrolled in 17 population studies

Objective:Searching for a prognostic cut-off value of serum uric acid (SUA) in predicting incident heart failure (HF) in a large regional-based Italian cohort of men and women in the frame of the URRAH study (URic Acid Right for heArt Health).Design and method:The ongoing large database URRAH collec

We have read with interest the manuscript by Salman et al. 1, who investigated different therapeutic approaches to treat spontaneous bacterial peritonitis (SBP) in patients with cirrhosis. The authors evaluated haemodynamic changes during SBP, showing an increase in cardiac output (CO) and a contemp

Summary Background and aims The possible effect of caffeine as an enhancer of cognitive performance, particularly that on abstract reasoning, has never been studied in an epidemiological setting, especially in relation to –163C>A polymorphism of CYP1A2 gene, largely controlling caffeine metabolism. Aim of this study was to ascertain whether in general population free chronic caffeine intake modifies abstract reasoning, and if this effect is influenced by the above mentioned genotype, by age, schooling, ethanol intake and smoking habits. Methods We studied 1374 unselected men and women aged 51 ± 15 years (range 18–89) from a general population. Daily caffeine intake deriving from coffee, tea, chocolate or cola was calculated from an anamnestic questionnaire and from a 7-day dietary diary. Abstract reasoning was measured in the frame of a neuropsychological assessment as the ability to find a concept linking two words indicating objects or actions and explaining how they were connected. Results In age-schooling-adjusted linear regression, the higher the caffeine intake, the better the abstraction score. Abstract reasoning depended on caffeine in the –163C>A CC homozygous only (so-called slow metabolizers), where it was higher in the 3rd tertile of caffeine intake. Age and ethanol reduced while smoking and schooling enhanced this association. The interaction term between caffeine and the –163C>A polymorphism was accepted in linear regressions. Caffeine consumption resulted innocuous for the A-carriers (so-called fast metabolizers). Conclusions In general population, a positive association between caffeine intake and abstract reasoning exists in the CC homozygous of the –163C>A polymorphism of CYP1A2 gene.

See related article, pp 103–110 The role of β-blockers on patients with a diagnosis of diabetes mellitus is controversial. They have been considered time-to-time neutral or able to induce hypoglycemia or, on the contrary, hyperglycemia. Physicians learned early in the β-blocking era to fear the reduction of the peripheral effects of hypoglycemia that accompanied β-blockade as a consequence of its antiadrenergic effects.1,2 The initial signs of an incipient hypoglycemia (such as peripheral tremulousness and tachycardia) could be masked, and patients remained unaware of a potential danger, such as severe hypoglycemia. Moreover, via an action on muscle and liver, β2-blockade can suppress glycogenolysis, which prevents correction of hypoglycemia. Later, many data and meta-analysis were shown about the beneficial or adverse effects of β-blockers in diabetes mellitus. These studies were often biased by the fact that patients under treatment or with comorbidities were commonly included. It was, therefore, difficult to discriminate the effects of β-blockade from those of the personal pathological profile.3 The study by Tsujimoto et al4 represents a step of this itinerary. It includes only patients with a diagnosis of diabetes mellitus without controls, and the number of subjects, particularly after case-to-case matching, is probably too small to avoid β error, but the results of the study are interesting enough to deserve some comments. Hypoglycemia is the most common metabolic complication experienced by patients with diabetes mellitus.1 The analysis by Tsujimoto et al4 does not concern directly a side effect of β-blockers, …

To determine if postmenopausal women have different arterial stiffness, blood pressure (BP) values, or metabolic patterns in comparison to fertile women and to men at a population level.This is a population-based epidemiologic study of 1853 representative men and women aged 18-95 years. Clinostatic humeral BP was measured using Omron 705CP. Aortic BP, augmentation index (AI), and pulse wave velocity (PWV) were determined using applanation tonometry. Body mass index (BMI) and subscapular skinfold thickness were used as measures of adiposity. Fasting and postload blood glucose, homeostasis model assessment (HOMA), low-density and high-density lipoprotein serum cholesterol (LDL-C and HDL-C) and triglycerides were assessed.Age was higher in postmenopausal women than in fertile women (68.8 ± 9.5 vs. 35.7 ± 10.2 years, p0.001), and BMI was 16% higher (p0.01) in the postmenopausal women after age adjustment. Humeral and aortic BP, carotid and radial AI, carotid-femoral PWV, BMI, LDL-C, LDL-C/HDL ratio, triglycerides, glucose tolerance, HOMA, and skinfold thickness were apparently higher in postmenopausal than in fertile women. Using multivariate analysis, however, all these differences were abolished after adjusting for confounders (age and, when appropriate, BMI), except for LDL-C, which remained 19% higher (p0.01) in postmenopausal women than in fertile women after adjusting for many confounders (age, BMI, cholesterol, ethanol intake, caloric intake, and triiodothyronine).Only LDL-C increases in postmenopausal women, whereas other differences attributed to menopause, including BP and arterial stiffness, seem to be confounding effects of age and BMI.

Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher ( P P =0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P =0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P =0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P =0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P =0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P =0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.

The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (≥90 mm Hg) or by daytime ABP (≥85 mm Hg), a history of cardiovascular disease, and persons P =0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79–1.53]; P =0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00; [95% CI: 1.43–2.79]; P P

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

It remains unknown whether diabetes and high blood pressure (BP) are simply additive risk factors for cardiovascular outcome or whether they act synergistically and potentiate one another. We performed 24-h ambulatory BP monitoring in 8494 subjects (mean age, 54.6 years; 47.0% women; 6.9% diabetic patients) enrolled in prospective population studies in 10 countries. In multivariable-adjusted Cox regression, we assessed the additive as opposed to the synergistic effects of BP and diabetes in relation to a composite cardiovascular endpoint by testing the significance of appropriate interaction terms. During 10.6 years (median follow-up), 1066 participants had a cardiovascular complication. Diabetes mellitus as well as the 24-h ambulatory BP were independent and powerful predictors of the composite cardiovascular endpoint. However, there was no synergistic interaction between diabetes and 24-h, daytime, or nighttime, systolic or diastolic ambulatory BP (P for interaction, 0.07P0.97). The only exception was a borderline synergistic effect between diabetes and daytime diastolic BP in relation to the composite cardiovascular endpoint (P=0.04). In diabetic patients, with normotension as the reference group, the adjusted hazard ratios for the cardiovascular endpoint were 1.35 (95% confidence interval (CI), 0.87-2.11) for white-coat hypertension, 1.78 (95% CI, 1.22-2.60) for masked hypertension and 2.44 (95% CI, 1.92-3.11) for sustained hypertension. The hazard ratios for non-diabetic subjects were not different from those of diabetic patients (P-values for interaction, 0.09P0.72). In conclusion, in a large international population-based database, both diabetes mellitus and BP contributed equally to the risk of cardiovascular complications without evidence for a synergistic effect.Hypertension Research advance online publication, 10 February 2011; doi:10.1038/hr.2011.6. ispartof: Hypertension research : official journal of the Japanese Society of Hypertension vol:34 issue:6 pages:714-721 ispartof: location:England status: published

To analyze sex-specific relative and absolute risks associated with blood pressure (BP), we performed conventional and 24-hour ambulatory BP measurements in 9357 subjects (mean age, 52.8 years; 47% women) recruited from 11 populations. We computed standardized multivariable-adjusted hazard ratios for associations between outcome and systolic BP. During a course of 11.2 years (median), 1245 participants died, 472 of cardiovascular causes. The number of fatal combined with nonfatal events was 1080, 525, and 458 for cardiovascular and cardiac events and for stroke, respectively. In women and men alike, systolic BP predicted outcome, irrespective of the type of BP measurement. Women compared with men were at lower risk (hazard ratios for death and all cardiovascular events=0.66 and 0.62, respectively; P P =0.020) and the relations of total mortality ( P =0.023) and all cardiovascular ( P =0.0013), cerebrovascular ( P =0.045), and cardiac ( P =0.034) events with nighttime BP were steeper in women than in men. Consequently, per a 1-SD decrease, the proportion of potentially preventable events was higher in women than in men for all cardiovascular events (35.9% vs 24.2%) in relation to 24-hour systolic BP (1-SD, 13.4 mm Hg) and for all-cause mortality (23.1% vs 12.3%) and cardiovascular (35.1% vs 19.4%), cerebrovascular (38.3% vs 25.9%), and cardiac (31.0% vs 16.0%) events in relation to systolic nighttime BP (1-SD, 14.1 mm Hg). In conclusion, although absolute risks associated with systolic BP were lower in women than men, our results reveal a vast and largely unused potential for cardiovascular prevention by BP-lowering treatment in women.

A blood glucose (BG) fall after an oral glucose load has never been described previously at a population level. This study was aimed at looking for a plasma glucose trend after an oral glucose load for possible blood glucose fall if any, and for its impact on coronary mortality at a population level.In subjects from an unselected general population, BG and insulin were detected before and 1 and 2h after a 75-g oral glucose load for insulin sensitivity and β-cell function determination. Blood pressure, blood examinations and left ventricular mass were measured, and mortality was monitored for 18.8±7.7 years. According to discriminant analysis, the population was stratified into cluster 0 (1-h BGfasting BG; n=497) and cluster 1 (1-h BG ≥ fasting BG; n=1733). To avoid any interference of age and sex, statistical analysis was limited to two age-gender-matched cohorts of 490 subjects from each cluster (n=940). Subjects in cluster 0 showed significantly higher insulin sensitivity and β-cell function, lower visceral adiposity and lower blood pressure values. Adjusted coronary mortality was 8 times lower in cluster 0 than 1 (p0.001). The relative risk of belonging to cluster 1 was 5.40 (95% CI 2.22-13.1).It seems that two clusters exist in the general population with respect to their response to an oral glucose load, independent of age and gender. Subjects who respond with a BG decrease could represent a privileged sub-population, where insulin sensitivity and β-cell function are better, some risk factors are less prevalent, and coronary mortality is lower.

BACKGROUND: We and other investigators previously reported that isolated nocturnal hypertension on ambulatory measurement (INH) clustered with cardiovascular risk factors and was associated with intermediate target organ damage. We investigated whether INH might also predict hard cardiovascular endpoints. METHODS AND RESULTS: We monitored blood pressure (BP) throughout the day and followed health outcomes in 8711 individuals randomly recruited from 10 populations (mean age 54.8 years, 47.0% women). Of these, 577 untreated individuals had INH (daytime BP /=120/70 mmHg) and 994 untreated individuals had isolated daytime hypertension on ambulatory measurement (IDH; daytime BP >/=135/85 mmHg and night-time BP

Importance of the field: Populations, the world over, age. Prevalence of hypertension increases with advancing age. Despite the advances over the past 30 years, there are still unresolved issues regarding antihypertensive therapy in the elderly. Areas covered in this review: The present review discusses the available evidence supporting treatment of hypertension in the elderly. What the reader will gain: In the 1980s and 1990s, a number of trials were performed and proved that active treatment of hypertension in individuals above the age of 60 - 65 years, compared with placebo or no treatment, reduces the risk of complications. In the 1990s, the same was proven in patients specifically affected with isolated systolic hypertension, the predominant form of hypertension in the elderly. The subsequent years witnessed the publication of trials that showed that most antihypertensive drugs are capable of substantially reducing risk. Finally, treatment of hypertension in the very elderly was proven to be beneficial. Take home message: In spite of these advances, we still lack evidence in elderly patients with mild isolated systolic hypertension and are therefore in need of a properly designed, randomized, placebo-controlled trial. ispartof: Expert Opinion on Pharmacotherapy vol:11 issue:16 pages:2609-2617 ispartof: location:England status: published

In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted ( P ≤0.03) total (HR: 1.14) and cardiovascular (HR: 1.21) mortality and all types of fatal combined with nonfatal end points (HR: ≥1.07) with the exception of cardiac and coronary events (HR: ≤1.02; P ≥0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted ( P P ≥0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added

Cardiovascular disease remains the leading cause of death worldwide. In this review, we briefly summarize new insights on the modulation of genetic cardiovascular risk by host factors such as sex and age and lifestyle factors such as salt intake. As phenotypes (genotypes) of interest, we considered left ventricular structure and function (ADD1 Gly460Trp; AGTR2 G1675A; ACE D/I), the incidence of heart failure (ADD1 Gly460Trp), heart rate variability (CYP11B2 C-344T; AGTR1 A1166C), carotid distensibility (IL6 G-174C), and serum lipid levels (APOE ɛ 2/ ɛ 3/ ɛ 4; APOA1 A 75G). In each case, the associations with the genetic cardiovascular risk factor were modulated by sex, age, sodium intake, or a combination thereof. These interactions highlight that genetic risk factors and phenotype-genotype associations can only be interpreted within their ecogenetic context. Perhaps a better understanding of these phenomena will lead researchers to target in a more specific way the pathophysiologic mechanisms operating within each individual.

The question on whether the electrocardiographic criteria are reliable for detection of left ventricular hypertrophy (LVH) and play a role in predicting outcome is open. Answer can only proceed from population-based studies over unselected people followed up for years. In this study, 1,699 subjects from general population underwent echocardiogram and standard electrocardiogram (ECG) codified for LVH with Minnesota code and with other five methods. Other items were also recorded and used as covariables. Left ventricular mass index (LVMI) was 127.6 +/- 44.9 g m(-2) in men and 120.8 +/- 41.2 g m(-2 )in women, and correlated directly with age in both genders. Prevalence of echocardiographic LVH was 36.6% in men and 53.4% in women. LVMI correlated directly with the Sokolow-Lyon score in both genders at any age, with the Romhilt-Estes, Cornell and R(aVL) scores in all subjects but elderly men, and with the Lewis score in men and women agedor =69 years. Sensitivity and the predictive value of electrocardiographic tests, as well as the prevalence of LVH diagnosed with electrocardiographic criteria, were always low. Specificity was high for all the tests, and in particular for the Cornell index. Only when diagnosed with echocardiogram or with the Sokolow-Lyon criterion, LVH was an independent predictor of mortality. We conclude that electrocardiographic tests cannot be used as a surrogate of echocardiogram in detecting LVH in the general population because their positive predictive value (PPV) is unacceptably low. On the contrary, they could replace echocardiography in the follow up and for prediction of outcome, when LVH has previously been correctly diagnosed with other methods.

OBJECTIVES: The 825T allele of the GNB3 gene is implicated in adipose distribution, predisposing to obesity and hypertension. Menopause is also considered a condition leading to excess adiposity and hypertension. The aim of the present study was to clarify whether the effects of menopause on body weight and blood pressure are influenced by the C825T polymorphism of the GNB3 gene. METHODS: The study involved 1339 subjects (43% men) aged 18-95 years, genotyped at the GNB3 825 locus, undergoing, in an epidemiological population-based frame, questionnaire, anthropometrics and blood examinations. RESULTS: Mean skinfold thickness (MST), truncal obesity and excess subcutaneous adiposity (MST greater than median) were higher in women than in men. A significant interaction was detected between menopausal status and the C825T polymorphism (Pint > 0.0001). MST, truncal obesity and excess subcutaneous adiposity were lower in CC fertile than menopausal women, but were comparable in TT fertile and menopausal women. In a multivariate logistic model for excess subcutaneous adiposity, the relative risk of menopause was 4.12 (95% confidence interval 2.35-7.22) in CC women but was insignificant in the other two genotypes. In fertile women only, higher systolic blood pressure (SBP) was detected in TT than in CC genotypes. CONCLUSION: An interaction exists between the C825T polymorphism and menopause in controlling body adiposity and blood pressure in women. Adiposity and SBP are higher in menopausal than in fertile women, provided they have the CC genotype. TT fertile women show the same adiposity as those in menopause. Men have the same excess adiposity as menopausal women, independent of the GNB3 genotype.

Late-systolic loading of the left ventricular (LV) is determined by arterial wave reflections and central vascular stiffening. We, therefore, investigated the relationship between various Doppler indexes reflecting LV systolic and diastolic function and arterial stiffness in the framework of a large population study of randomly recruited study participants.In 1233 study participants (51.7% women; mean age, 48 years; 41.5% hypertensive), using conventional and tissue Doppler imaging, we measured: the transmitral early (E) and late (A) diastolic velocities; tissue Doppler imaging systolic and early (e') and late diastolic mitral annular velocities; and end-systolic longitudinal and radial strain. Using applanation tonometry, we assessed central pulse pressure (cPP), augmentation pressure and carotid-femoral pulse wave velocity.After full adjustment, transmitral E and A peaks increased with augmentation pressure and cPP (P less than 0.0001) and e' was positively associated with cPP (P = 0.013). The E/e' ratio increased significantly with augmentation pressure (P less than 0.0001), cPP (P less than 0.0001) and pulse wave velocity (P = 0.048). Although accounting for covariables, all arterial indexes were on average significantly higher in the diastolic dysfunction group with elevated filling pressure (n = 171) when compared to participants with normal diastolic function (n = 961; P ≤ 0.0004) or with impaired relaxation (n = 101; P ≤ 0.008). Longitudinal strain decreased independently with mean arterial pressure (P = 0.03). The correlation between radial strain and the arterial indexes shifted from positive at middle age (50-60 years) to negative at older (P less than 0.0001 for interaction).Our study underscored the importance of arterial characteristics as a mediator of LV systolic and diastolic dysfunction. We demonstrated an age-dependent relationship between radial strain and indexes of arterial stiffness.