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In resistant hypertensive patients acute carotid baroreflex stimulation is associated with a blood pressure (BP) reduction, believed to be mediated by a central sympathoinhbition.The evidence for this sympathomodulatory effect is limited, however. This meta-analysis is the first to examine the sympathomodulatory effects of acute carotid baroreflex stimulation in drug-resistant and uncontrolled hypertension, based on the results of microneurographic studies. The analysis included 3 studies assessing muscle sympathetic nerve activity (MSNA) and examining 41 resistant uncontrolled hypertensives. The evaluation included assessment of the relationships between MSNA and clinic heart rate and BP changes associated with the procedure. Carotid baroreflex stimulation induced an acute reduction in clinic systolic and diastolic BP which achieved statistical significance for the former variable only [systolic BP: -19.98 mmHg (90% CI, -30.52, -9.43), P < 0.002], [diastolic BP: -5.49 mmHg (90% CI, -11.38, 0.39), P = NS]. These BP changes were accompanied by a significant MSNA reduction [-4.28 bursts/min (90% CI, -8.62, 0.06), P < 0.07], and by a significant heart rate decrease [-3.65 beats/min (90% CI, -5.49, -1.81), P < 0.001]. No significant relationship was detected beween the MSNA, systolic and diastolic BP changes induced by the procedure, this being the case also for heart rate. Our data show that the acute BP lowering responses to carotid baroreflex stimulation, although associated with a significant MSNA reduction, are not quantitatively related to the sympathomoderating effects of the procedure. This may suggest that these BP effects depend only in part on central sympathoinhibition, at least in the acute phase following the intervention., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Findings regarding the association between Cardio-Ankle Vascular Index (CAVI) and cardiac hypertension-mediated organ damage (HMOD), such as left ventricular hypertrophy (LVH) assessed by echocardiography, in elderly hypertensive patients are scanty. We sought to investigate this issue in the hypertensive fraction of the general population treated with anti-hypertensive drugs enrolled in the Pressioni Monitorate E Loro Associazioni (PAMELA) study., Methods: The study included 239 out of 562 participants who attended the second and third surveys of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory blood pressure (BP), blood examinations, echocardiography, and CAVI measurements., Results: In the whole study sample (age 69 ± 9 years, 54% males), CAVI was positively correlated with age, office, home, ambulatory systolic BP, LV mass (LVM) index, and negatively associated with body mass index (BMI). In multivariate analysis, CAVI was associated with the LVM index (P < 0.05) independently of major confounders. The participants with LVH exhibited significantly higher CAVI (10.6 ± 2.8 vs. 9.2 ± 1.8 m/s P < 0.001), larger left atrial diameter, and lower LV ejection fraction values than their counterparts without it. The CAVI value of 9.4 m/s was the best cut-off for prediction of LVH in the whole sample., Conclusions: Our study provides new evidence of an independent association between CAVI and LVH in treated elderly hypertensive patients and suggests that the use of this metric of arterial stiffness could not only be used to evaluate vascular damage but also to stratify the risk of LVH., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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.

In patients with end-stage renal disease (ESRD) undergoing haemodialysis, hypertension is of common detection and frequently inadequately controlled. Multiple pathophysiological mechanisms are involved in the development and progression of the ESRD-related high blood pressure state, which has been implicated in the increased cardiovascular risk reported in this hypertensive clinical phenotype. Renal sympathetic efferent and afferent nerves play a relevant role in the development and progression of elevated blood pressure values in patients with ESRD, often leading to resistant hypertension. Catheter-based bilateral renal nerves ablation has been shown to exert blood pressure lowering effects in resistant hypertensive patients with normal kidney function. Promising data on the procedure in ESRD patients with resistant hypertension have been reported in small scale pilot studies. Denervation of the native non-functioning kidney's neural excitatory influences on central sympathetic drive could reduce the elevated cardiovascular morbidity and mortality seen in ESRD patients. The present review article will focus on the promising results obtained with renal denervation in patients with ESRD, its mechanisms of action and future perspectives in these high risk patients., (© 2024. The Author(s).)

Objectives: In any treated hypertensive patient office blood pressure (BP) values may differ between visits and this variability (V) has an adverse prognostic impact. However, little information is available on visit-to-visit 24-h BPV., Methods: In 1114 hypertensives of the ELSA and PHYLLIS trials we compared visit-to-visit office and 24-h mean BPV by coefficient of variation (CV) of the mean systolic (S) and diastolic (D) BP obtained from yearly measurements during a 3-4 year treatment period. Visit-to-visit BPV during daytime and night-time were also compared., Results: Twenty-four-hour SBP-CV was about 20% less than office SBP-CV ( P  < 0.0001). SBP-CV was considerably greater for the night-time than for the daytime period (20%, P  < 0.0001). Results were similar for DBP and in males and females, older and younger patients, patients under different antihypertensive drugs or with different baseline or achieved BP values. In the group as a whole and in subgroups there was significant correlations between office and 24-h BP-CV but the correlation coefficients was weak, indicating that office SBP or DBP CV accounted for only about 1-4% of 24-h SBP or DBP-CV values., Conclusion: Twenty-four-hour mean BP across visits is more stable than across visit office BP. Visit-to-visit office and 24-h BPV are significantly related to each other, but correlation coefficients are low, making visit-to-visit office BP variations poorly predictive of the concomitant 24-h BP variations and thus of on-treatment ambulatory BP stability., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Epidemiological studies have unequivocally shown that elevated heart rate values measured at rest have an adverse prognostic impact in the hypertensive patient, being associated with an increased risk of cardiovascular events and complications. In recent years new data have been collected on this issue, strengthening the clinical relevance of elevated heart rate as a specific hypertensive phenotype. The present paper will review old and new data on the prognostic importance of resting tachycardia in the hypertensive patient. It will also examine the role of the sympathetic nervous system in the development of this alteration as well as its therapeutic implications. The different approaches to dynamically assess heart rate values in the clinical setting will be finally discussed., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Purpose of Review: To examine published and unpublished data documenting the role of sympathetic neural factors in the pathogenesis of different hypertensive phenotypes. These phenotypes relate to attended or unattended blood pressure measurements, to nighttime blood pressure profile alterations, and to resistant, pseudoresistant, and refractory hypertension. Results of original clinical studies as well as of recent meta-analyses based on the behavior of different sympathetic biomarkers in various hypertensive forms will be also discussed., Recent Findings: Studies performed in the past decade have shown that office blood pressure measurements, including in recent years those characterizing unattended or attended blood pressure assessment, are associated with profound changes in the behavior of different sympathetic biomarkers. This is the case for the clinical hypertensive phenotypes characterized by alterations in the nocturnal blood pressure profile and by sleep duration abnormalities. This is also the case for the clinical conditions defined as resistant, refractory, and pseudoresistant hypertension. Data reviewed in the present paper highlight the relevance of sympathetic neural factors in the development and progression of different clinical hypertensive phenotypes. This suggests that a common hallmark of the majority of the essential hypertensive states detectable in current clinical practice is represented by the alteration in the sympathetic blood pressure control., (© 2023. The Author(s).)

Background and Aims: Chronic coffee consuption has been reported to be associated with a modest but significant increase in blood pressure (BP), although some recent studies have shown the opposite. These data, however, largely refer to clinic BP and virtually no study evaluated cross-sectionally the association between chronic coffee consuption, out-of-office BP and BP variability., Methods and Results: In 2045 subjects belonging to the population of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, we analyzed cross-sectionally the association between clinic, 24-hour, home BP and BP variability and level of chronic coffee consumption. Results show that when adjusted for confounders (age, gender, body mass index, cigarette smoking, physical activity and alcohol drinking) chronic coffee consumption does not appear to have any major lowering effect on BP values, particulary when they are assessed via 24-hour ambulatory (0 Cup/day: 118.5 ± 0.7/72.8 ± 0.4 mmHg vs 3 cups/day: 120.2 ± 0.4/74.8 ± 0.3 mmHg, PNS) or home BP monitoring (0 cup/day: 124.1 ± 1.2/75.4 ± 0.7 mmHg vs 3 cups/day: 123.3 ± 0.6/76.4 ± 0.36 mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2 mmHg), suggesting some pressor effects of coffee which vanish during nighttime. Both BP and HR 24-hour HR variability were unaffected., Conclusion: Thus chronic coffee consumption does not appear to have any major lowering effect either on absolute BP values, particulary when they are assessed via 24-hour ambulatory or home BP monitoring, or on 24-hour BP variability., (Copyright © 2023 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.)

Purpose: Renal denervation (RDN) exerts sympathoinhibitory effects. No information is available, however, on whether these effects have a regional or a more generalized behavior., Methods: In 14 patients with resistant hypertension (RHT, age 58.3 ± 2.2 years, mean ± SEM), we recorded muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively) using the microneurographic technique, before, 1 month, and 3 months after RDN. Measurements included clinic blood pressure (BP), heart rate (HR), 24-h BP and HR, as well as routine laboratory and echocardiographic variables. Ten age-matched RHT patients who did not undergo RDN served as controls., Results: MSNA, but not SSNA, was markedly higher in RHT. RDN caused a significant reduction in MSNA 1 month after RDN, with this reduction increasing after 3 months (from 68.1 ± 2.5 to 64.8 ± 2.4 and 63.1 ± 2.6 bursts/100 heartbeats, P < 0.05). This effect was not accompanied by any significant change in SSNA (from 13.1 ± 0.5 to 13.4 ± 0.6 and 13.3 ± 0.4 bursts/min, P = NS). No quantitative or, in some cases, qualitative relationship was found between BP and the MSNA reduction induced by RDN. No significant changes in various sympathetic markers were detected in the control group who did not undergo RDN and were followed for 3-months observation., Conclusions: These data provide the first evidence that RDN exerts heterogeneous effects on sympathetic cardiovascular drive, inducing a marked reduction in MSNA but not in SSNA, which appears to be within the normal range in this condition.These effects may depend on the different reflex modulation regulating neuroadrenergic drive in these cardiovascular districts., (© 2023. The Author(s).)

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

Objective: In the frame of the Uric Acid Right for Heart Health (URRAH) study, a nationwide multicenter study involving adult participants recruited on a regional community basis from all the territory of Italy under the patronage of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension, we searched for the cut-off values of the ratio between serum uric acid (SUA) and serum creatinine (sCr) able to predict cardiovascular (CV) events., Methods: Among 20 724 participants followed-up for 126 ± 64 months, after detecting cut-off by the receiver operating characteristic curves, we calculated by Cox models adjusted for confounders having CV events as dependent variable the hazard ratio (HR) of SUA/sCr > cut-off. We also verified if the role of cut-off varied with increasing SUA/sCr., Results: A plausible prognostic cut-off of SUA/sCr was found and was the same in the whole database, in men and in women (>5.35). The HR of SUA/sCr > cut-off was 1.159 (95% confidence interval [CI] 1.092-1.131, P < 0.03) in all, 1.161 (95% CI 1.021-1.335, P < 0.02) in men, and 1.444 (95% CI 1.012-1.113, P < 0.03) in women. In increasing quintiles of SUA/sCr the cut-offs were >3.08, >4.87, >5.35, >6.22 and >7.58, respectively. The HRs significantly increased from the 3rd to the 5th quintile (1.21, 95% CI 1.032-1.467, P = 0.018; 1.294, 95% CI 1.101-1.521, P = 0.002; and 1.642, 95% CI 1.405-1.919, P < 0.0001; respectively), that is, over 5.35, whereas the 2nd quintile was not significantly different from the 1st (reference)., Conclusion: Having SUA/sCr >5.35 is an independent CV risk indicator both in men and women. The cut-off is dynamic and significantly increases with increasing SUA/sCr., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Aim: Little evidence is available on whether antihypertensive treatment lowers cardiovascular risk in white-coat hypertension (WCH). Protection might be indirectly inferred, however, from the blood pressure (BP) effects of treatment as in trials BP reduction is linearly related to outcome reduction. We analyzed the effect of antihypertensive treatment on office and ambulatory BP in WCH using data from the Plaque HYpertension Lipid-Lowering Italian Study (PHYLLIS)., Methods: : Office and ambulatory blood pressure were measured in 470 hypertensive patients randomized to fosinopril or hydrochlorothiazide alone or combined with a statin before treatment and at 6 month or yearly intervals during 2.6 years of follow-up. Patients were divided into two groups according to whether before randomization to treatment office and 24-h mean BP were elevated (sustained hypertension) or office BP was elevated but 24-h BP values were normal (WCH)., Results: : In both sustained hypertension and WCH antihypertensive treatment was associated with an early marked office BP reduction, which persisted virtually unchanged throughout the treatment period. In contrast, 24-h (and day and night) BP showed a marked and persistent treatment-related fall in sustained hypertension but no change in WCH. The results were similar when data were separately analyzed in patients under fosinopril or diuretic, with or without statin treatment., Conclusion: : In WCH, antihypertensive treatment can effectively and durably reduce office BP. This reduction is accompanied by the inability to lower ambulatory BP from the normal values characterizing this condition at baseline. This appears to be unrelated to the type of treatment employed., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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

We examined in 11 young subjects (age 29.7±3.6 years, mean±SEM) whether carotid baroreceptor stimulation via the neck chamber device may affect central venous pressure (CVP), thus potentially involving other reflexogenic areas in the examined responses. Application of progressively greater neck chamber subatmospheric pressures caused a progressive lengthening in RR interval, which reached a peak at the maximal value of negative neck chamber pressure applied. This was accompanied by significant and progressively greater reduction in CVP values when the data were calculated considering the early changes occurring within the first 2 seconds of the stimulus. There was a weak correlation between the early changes in CVP and the RR interval responses when all stimuli were pooled together (r = 0.32, P < .05). The results of the present study suggest that the neck chamber technique employed to assess carotid baroreceptor-heart rate sensitivity can transiently affect via the CVP reduction cardiopulmonary receptors activity, which may participate at the integrated reflex responses., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

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Aim: Available evidence on regression of left ventricular (LV) hypertrophy in patients with primary aldosteronism after unilateral adrenalectomy is scanty. We performed a systematic meta-analysis of echocardiographic studies to provide an updated and comprehensive information on this issue., Methods: The PubMed, OVID-MEDLINE and Cochrane library databases were analyzed to search English-language articles published from 1 January 1990 up to 30 June 2020. Studies were identified by using MeSH terms and crossing the following search items: 'primary aldosteronism' 'Conn's syndrome' 'adrenalectomy', with 'cardiac damage', 'hypertensive heart disease' 'left ventricular mass', 'left ventricular hypertrophy', 'left ventricular hypertrophy regression', 'echocardiography'., Results: A total of 629 hypertensive patients with primary aldosteronism (mean age 49 years, 45% men) were included in 14 studies. Baseline and postintervention pooled mean LV mass/BSA values were 134 ± 4 and 108 ± 3 g/m2 [standard means difference (SMD) -0.42 ± 0.05, confidence interval (CI) -0.52/-0.32, P < 0.0001]; corresponding values for LV mass/h2.7 were 56 ± 2 and 49 ± 1 g/h2.7 (SMD -0.45 ± 0.06, CI -0.52/-0.36, P < 0.0001). Adrenalectomy, followed by a marked decrease in blood pressure, was associated with a decrease in relative wall thickness (SMD -0.17 ± 0.06, CI -0.31/-0.03, P < 0.01) as well as in the number of antihypertensive drugs (SMD -0.45 ± 0.04, CI -0.50-0.32, P < 0.0001)., Conclusion: The present meta-analysis suggests that adrenalectomy in patients with primary aldosteronism exerts a beneficial effect on LV structure and geometry by reducing the burden of LV hypertrophy and LV concentric geometry., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: To review the results of studies of the effects of dialysis and kidney transplantation on the autonomic nervous system alterations that occur in chronic kidney disease., Recent Findings: Vagal control of the heart mediated by arterial baroreceptors is altered early in the course of the renal disease. Sympathetic activation occurs, with increases in resting heart rate, venous plasma norepinephrine levels, muscle sympathetic nerve traffic, and other indirect indices of adrenergic drive. The magnitude of the changes reflects the clinical severity of the kidney disease. Both the sympathetic and parasympathetic alterations have a reflex origin, depending on the impairment in baroreflex and cardiopulmonary reflex control of the cardiovascular system. These alterations are partially reversed during acute hemodialysis, but the responses are variable depending on the specific type of dialytic treatment that is employed. Renal transplantation improves reflex cardiovascular control, resulting in sympathoinhibition following renal transplantation if the native kidneys are removed. Sympathoinhibitory effects have been also reported in renal failure patients after bilateral renal denervation. Assessment of autonomic nervous system responses to dialysis and renal transplantation provides information of clinical interest, given the evidence that autonomic alterations are involved in the development and progression of cardiovascular complications, as well as in the prognosis of chronic kidney disease.

Objective: Although the relationship between hyperuricemia and cardiovascular events has been extensively examined, data on the role of diuretic-related hyperuricemia are still scanty. The present study was designed to collect information on the relationship between diuretic-related hyperuricemia and cardiovascular events., Methods: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, observational cohort study involving data on individuals recruited from all the Italy territory under the patronage of the Italian Society of Hypertension with an average follow-up period of 122.3 ± 66.9 months. Patients were classified into four groups according to the diuretic use (yes vs. no) and serum uric acid (SUA) levels (higher vs. lower than the median value of 4.8 mg/dl). All-cause death, cardiovascular deaths and first cardiovascular event were considered as outcomes., Results: Seventeen thousand, seven hundred and forty-seven individuals were included in the analysis. Mean age was 57.1 ± 15.2 years, men were 45.3% and SBP and DBP amounted to 144.1 ± 24.6 and 85.2 ± 13.2 mmHg. 17.2% of individuals take diuretics of whom 58% had SUA higher than median value. Patients with hyperuricemia without diuretic use served as reference group. In multivariate adjusted analysis (sex, age, SBP, BMI, glucose, total cholesterol, and glomerular filtration rate) individuals with hyperuricemia and diuretic use exhibit a similar risk for the three outcomes as compared with the reference group., Conclusion: Our study showed that diuretic-related hyperuricemia carry a similar risk of cardiovascular events and all-cause mortality when compared with individuals that present hyperuricemia in absence of diuretic therapy., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Conclusive evidence demonstrates that the sympathetic nervous system activation is a hallmark of congestive heart failure. This has been shown via a variety of biochemical, neurophysiological, and neuroimaging approaches for studying human sympathetic neural function. The sympathetic activation appears to be an early phenomenon in the clinical course of the disease, closely related to its severity and potentiated by the concomitant presence of other comorbidities, such as obesity, diabetes mellitus, metabolic syndrome, hypertension, and renal failure. The adrenergic overdrive in heart failure is associated with other sympathetic abnormalities, such as the downregulation of beta-adrenergic adrenoreceptors at cardiac level, and exerts unfavorable consequences on the cardiovascular system. These include the endothelial dysfunction, the development of left ventricular hypertrophy, the atherosclerosis development, as well as the generation of atrial and ventricular arrhythmias, and, at very extreme levels of sympathetic activation, the occurrence of microscopic myocardial necrosis. Given the close direct independent relationships detected in heart failure between sympathetic activation and mortality, the adrenergic overdrive has become a target of neuromodulatory therapeutic interventions, which include non-pharmacological, pharmacological, and device-based interventions. For some of these approaches (specifically bilateral renal nerves ablation and carotid baroreceptor stimulation), additional studies are needed to better define their impact on the clinical course of the disease.

Aim: Few echocardiographic studies have focused on regression of left ventricular hypertrophy (LVH) in patients with renal artery stenosis after revascularization, with inconsistent results. We performed a systematic meta-analysis of these studies in order to offer a comprehensive information on this topic., Methods: The PubMed, OVID-MEDLINE, and Cochrane library databases were analyzed to search English-language articles published from 1 January 1990 up to 31 March 2020. Studies were identified by crossing the following terms: 'renal artery stenosis', 'renovascular hypertension', 'fibromuscular dysplasia', 'renal artery stenting', 'renal artery surgery' with 'cardiac damage', 'hypertensive heart disease' 'left ventricular mass', 'left ventricular hypertrophy', 'echocardiography'., Results: A total of 726 hypertensive patients with renal artery stenosis (mean age 61 years, 64% men, 98% treated, 10% with fibromuscular dysplasia) were included in 13 studies. Baseline and postintervention pooled mean LVM values were 220 ± 15 and 203 ± 19 g, respectively (SMD -0.24 ± 0.06, CI -0.37 to -0.21, P<0.0001); corresponding values for LV mass index were 129.0 ± 6 and 115 ± 7 g/m, respectively (SMD -0.28 ± 0.04, CI -0.36 to 0.21, P < 0.0001). Renal revascularization was associated with a 40% lower risk of LVH. This trend was accompanied by a reduction in the number of antihypertensive drugs (SMD -0.27 ± 0.04, CI -0.37 to 0.17, P < 0.0001)., Conclusion: The present meta-analysis suggests that renal artery revascularization added to antihypertensive therapy promotes a favourable effect on LV structure, as reflected by a significant decrease in absolute and indexed LV mass index as well by a lower risk of LVH. Limitations include: high prevalence of modest renal artery stenosis (≥50%); small sample of fibromuscular dysplasia; lack of randomized design of most studies.

Objective: We aimed to investigate left atrial phasic function in the recently diagnosed hypertensive patients and determine association between circadian blood pressure (BP) patterns and left atrial function., Methods: The present study involved 256 untreated hypertensive patients who underwent 24-h ambulatory BP monitoring and comprehensive echocardiographic examination. All patients were divided into four groups according to the percentage of nocturnal BP drop (dippers, extreme dippers, nondippers and reverse dippers)., Results: There was no significant difference in daytime BPs between the observed groups, whereas night-time BPs significantly and gradually increased from extreme dippers and dippers, across nondippers, to reverse dippers. Total, passive and active left atrial emptying fractions that correspond with left atrial reservoir, conduit and contractile function were lower in nondippers and reverse dippers than in dippers and extreme dippers. Reservoir and contractile left atrial strains were lower in reverse dippers than in dippers and extreme dippers, whereas conduit left atrial strain was lower in reverse dippers in comparison with extreme dippers. Nondipping and reverse dipping BP patterns were, independently of age, sex, nocturnal BPs, left ventricular mass index, E/e', associated with reduced reservoir function. Nevertheless, only reverse dipping profile was independently of other circadian BP profiles, nocturnal BP, demographic and echocardiographic parameters related with reduced conduit and contractile functions., Conclusion: Nondipping and reverse dipping BP patterns were related with impaired left atrial phasic function. However, reverse pattern was the only circadian profile that was independently of other clinical parameters, including night-time BP, associated with decreased reservoir, conduit and contractile function.

Findings regarding long-terms variations in blood pressure (BP) taken in different setting (ie, office, home, and ambulatory BP) in the community are scanty. We sought to assess this issue in members of the general population enrolled in the PAMELA (Pressioni Monitorate E Loro Associazioni) study. The study included 562 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory BP, and standard blood examinations. Office, home, and 24-hour systolic BP over the 25-year interval between the first and third survey increased in a parallel way (ie, 12%, 10%, and 15.5%). The increments in office, home, and 24-hour diastolic BP were lower than the systolic BP ones (ie, 3.3%, 5.6%, and 6.1%). Thus, the combined changes in systolic BP and diastolic BP from the first to the third data collection resulted in a marked increase in pulse pressure (ie, 29%, 19%, and 30%). The prevalence of hypertension assessed at office visits and out-of-office either by self-BP measurements at home and ambulatory blood pressure monitoring increased ≈3 to 4× (3.1 office, 3.3 home, 3.9 ABPM, respectively). This trend was associated with adiposity indexes and worsening of the glucose profile. This community-based longitudinal study suggests that the progressive and marked increase in hypertension with age, consistently documented with different BP measurement methods, represents an epochal challenge for the prevention of cardiovascular diseases, due to the rapid growth the elderly population worldwide.

Aim: Information regarding the association of hypertension-mediated organ damage (HMOD) with extreme dipping pattern is scanty and not univocal. We sought to assess the clinical correlates of this blood pressure (BP) phenotype and its relationship with cardiac HMOD in the general population belonging to Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study., Methods: The present analysis included all participants with good-quality ABPM recordings with reliable echocardiography at entry., Results: A total of 792 out of 1597 patients (49.6%) exhibited an extreme dipping pattern (155 had a night-time reduction in both SBP and DBP at least 20% compared with daytime values and 637 a night-time reduction in DBP at least 20%); 34.2% were dippers and 16.2% nondippers. Left ventricular mass (LVM) indexed to height and LV hypertrophy (LVH) prevalence rates increased progressively from diastolic extreme dipping (14%), dipper (17%), systolic/diastolic extreme dipping (21%) to nondipper group (27%). However, after adjusting for confounders, statistical differences in both LVMI and LVH rates among the four groups disappeared. Similar results were obtained for LVM indexed to body surface area and absolute/indexed left atrial diameter., Conclusion: Extreme dipping pattern is a BP phenotype highly frequent in the general population largely consisting of middle-aged individuals without prevalent cardiovascular disease. In this population, the extreme dipping pattern is not associated with an increased risk of cardiac HMOD, which suggests that the mechanisms invoked for the potential adverse cardiovascular effects of this condition (i.e. nocturnal hypoxemia, low-grade myocardial inflammation, coronary hypoperfusion, sympathetic activation at early morning, etc.) are not operative.

Aim: Findings regarding the association of left ventricular mass (LVM) and new-onset hypertension are based on blood pressure measured in the office. We sought to assess the value of LVM in predicting in-office and out-of-office incident hypertension in members of the general population enrolled in the Pressioni Monitorate E Loro Associazioni study., Methods: The study included participants with normal office (n = 792), home (n = 714) and 24-h (n = 825) ambulatory blood pressure (ABP) at baseline evaluation who had a readable echocardiogram at entry and at the end of follow-up. Each normotensive group was divided into quartiles of LVM indexed (LVMI) to height., Results: Over a follow-up of 148 months cumulative incidence of new office, home and 24-h ABP hypertension were 35.9, 30.7 and 36.1%, respectively. In fully adjusted models (including age, sex, BMI change during follow-up, baseline serum glucose, creatinine, total cholesterol office, home and 24-h SBP and DBP). higher LVMI values (i.e. the highest vs. the lowest quartile) were independently associated with an increased risk of home [odds ratio (OR) = 2.14, 95% confidence interval (CI) 1.21-3.77, P = 0.008] and 24-h ABP hypertension (OR = 1.70, 95% CI 1.05-2.76, P = 0.03). This was not the case for new-onset office hypertension (OR = 1.61, 95% CI 0.94-2.74, P = 0.07)., Conclusion: Our study provides the first evidence that in normotensive individuals the magnitude of LVMI is independently associated with the risk of incident out-of-office hypertension.

True drug-resistant hypertension (RHT) is characterized by a marked neuroadrenergic activation and reflex alterations compared with the nonresistant hypertensive state. It is unknown however, whether this behavior is specific for the RHT state or is also shared by apparent RHT (ARHT). In 38 middle-age patients with RHT, 44 treated essential controlled hypertensives (HT) and 32 ARHT; we evaluated sphygmomanometric, beat-to-beat (Finapres) and 24-hour (Spacelabs) blood pressure, heart rate and muscle sympathetic nerve traffic (microneurography). Measurements included plasma aldosterone, plasma norepinephrine, homeostasis model assessment index, and spontaneous baroreflex-muscle sympathetic nerve traffic sensitivity. All the various above-mentioned blood pressure values were significantly greater in both RHT and ARHT as compared with HT, while 24-hour blood pressure was significantly lower in ARHT as compared with RHT. In ARHT, muscle sympathetic nerve traffic was significantly lower than RHT (74.8±5.2 versus 89.2±4.8 bursts/100 hb, P <0.01) and similar to HT (69.7±4.8 bursts/100 hb, P =NS). RHT showed, at variance from the other 2 groups, greater plasma aldosterone and homeostasis model assessment index values and an impaired baroreflex function. In RHT, but not in ARHT and HT, muscle sympathetic nerve traffic was significantly and inversely related to baroreflex function ( r =-0.40, P <0.02) and directly to plasma aldosterone and homeostasis model assessment index values ( r =0.34-0.36, P <0.05). Plasma norepinephrine and heart rate values were not significantly different in the 3 groups. These data provide evidence that the marked sympathetic activation and baroreflex dysfunction detected in RHT is not present in ARHT, which displays a sympathetic and baroreflex profile superimposable to that seen in HT. These differences in the neurogenic function may have important clinical and therapeutic implications.

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.)

Introduction: Although improved during the past few years, blood pressure control remains sub optimal., Aim: The impact of follow-up assessment on blood pressure control was evaluated in a group of patients of the HYT (HYperTension survey), treated with a combination of different dihydropyridine calcium-channel blockers (CCBs regimen) and inhibitors of renin-angiotensin-aldosterone system (RAAS) and with uncontrolled blood pressure. This was obtained assessing (a) the rate of blood pressure control at 3 and 6 months of follow-up in the whole group of patients, (b) the rate of blood pressure control and the average blood pressure values in subjects treated with different DHP-CCBs regimen., Methods: From the 4993 patients with uncontrolled blood pressure, (BP ≥ 140/90 or ≥140/85 in patients with diabetes), 3729 (mean age 61.2 ± 11.5 years), maintained CCBs regimen combined wih RAAS blockers and were evaluated at 3 and 6 months follow-up. At each visit BP (semiautomatic device, Omron-M6, 3 measurements), heart rate, adverse events and treatment persistence were collected., Results: At 1st and 2nd follow-up the rate of controlled BP was 63.5 and 72.8% respectively (p < 0.05 vs 35.3% at baseline), whereas in diabetes was 32.5 and 37.9% respectively (p < 0.05 vs 20% at baseline). No differences in heart rate were observed. No differences in control rate were observed between the different CCBs regimen. The incidence of drugs related adverse events was 3.6%., Conclusions: These findings provide evidence that: (a) the follow-up of hypertensive patients under therapy increase the rate of blood pressure control; (b) there is no significant difference in the antihypertensive effect between different CCBs regimen;, ((c) lipophilic CCBs induce less ankle edema.)

Objective: Adrenergic activation and baroreflex dysfunction are common in established essential hypertension, elderly hypertension, masked and white-coat hypertension, resistant hypertension, and obesity-related hypertension. Whether this autonomic behavior is peculiar to established hypertension or is also detectable in the earlier clinical phases of the disease, that is, the high-normal blood pressure (BP) state, is still largely undefined, however., Methods: In 24 individuals with optimal BP (age: 37.1  ±  2.1 years, mean  ±  SEM) and in 27 with normal BP and 38 with high-normal BP, age matched with optimal BP, we measured clinic, 24-h and beat-to-beat BP, heart rate (HR), and muscle sympathetic nerve activity (MSNA) at rest and during baroreceptor stimulation and deactivation. Measurements also included anthropometric as well as echocardiographic and homeostasis model assessment (HOMA) index., Results: For similar anthropometric values, clinic, 24-h ambulatory, and beat-to-beat BPs were significantly greater in normal BP than in optimal BP. This was the case when the high-normal BP group was compared to the normal and optimal BP groups. MSNA (but not HR) was also significantly greater in high-normal BP than in normal BP and optimal BP (51.3  ±  2.0 vs. 40.3  ±  2.3 and 41.1 ± 2.6  bursts per 100  heartbeats, respectively, P < 0.01). The sympathetic activation seen in high-normal BP was coupled with an impairment of baroreflex HR control (but not MSNA) and with a significant increase in HOMA Index, which showed a significant direct relationship with MSNA., Conclusion: Thus, independently of which BP the diagnosis is based, high-normal BP is a condition characterized by a sympathetic activation. This neurogenic alteration, which is likely to be triggered by metabolic rather than reflex alterations, might be involved, together with other factors, in the progression of the condition to established hypertension.

Introduction: Although improved during the past few years, high blood pressure control still remains an unmet goal of antihypertensive drug treatment. Among different antihypertensive agents, calcium channel blockers (CCBs), either as monotherapy or in combination with other drugs are recommended by several guidelines for initiation and maintenance of antihypertensive treatment., Aim: The HYT-HYperTension survey, carried out in Turkey was aimed to assess (a) blood pressure control in hypertensive patients under treatment with dihydropyridine CCBs, either as monotherapy or in combination with other drugs and (b) the prevalence of blood pressure control in subgroups of patients with cardiovascular risk factors (previous cardiovascular disease, diabetes, renal disease, isolated systolic hypertension, visceral obesity, overweight, current smoking habit)., Methods: More than 7000 hypertensive patients (60.0 % men, mean age 61.2 ± 11.5 years), routinely visited by either a specialist or a non-specialist physician in the Primary Care Units of 26 cities across Turkey, were enrolled in the survey. Only patients treated with dihydropyridine-type CCBs, as mono- or combination therapy were included in the study, whereas individuals treated with non-dihydropyridine-type CCBs or with other drug classes (as monotherapy or combination therapy), were excluded. Demographic data (age, gender, height, weight, waist circumference, current smoker habit), clinical data and drug treatments were collected at each visit. Blood pressure was measured with a semiautomatic device (Omron-M6) with the patient in sitting position and after at least 5 min of rest. Measurements were repeated three times, at intervals of 5 min each other., Results: In the overall survey population blood pressure control (blood pressure <140/90 mmHg) was achieved in 31.7 % of patients and the average systolic and diastolic blood pressure was 145.3/88.2 mmHg. Prevalence of patients treated with dihydropyridine-type CCBs, either as monotherapy or combined with other drugs, was superimposable (51.6 vs 48.4 %, P = NS). Dihydropyridine-type CCBs were more frequently combined with drugs acting on the renin-angiotensin-aldosterone system (86.4 %), particularly with ACE-inhibitors (34.1 %) and angiotensin II receptor antagonists (52.3 %), while in 13.6 % of patients CCBs were combined with diuretics and/or beta-blockers. Diabetes mellitus was detected in 22.7 % of patients, obesity in 41.5 % and history of cardiovascular disease in 23.0 % (coronary artery disease in 19.2 % and stroke in 3.8 %). Blood pressure control was more difficult to be achieved in complicated hypertension, particularly when cigarette smoking, obesity, overweight, visceral obesity and renal disease were associated with hypertension., Conclusions: Taken together these findings provide evidence that dihydropyridine-type CCBs, particularly when combined with ACE-inhibitors or angiotensin II receptors blockers, allow to achieve a blood pressure control better than the one reported in the same geographic area by other treatment strategies based on different combinations of diuretics, beta-blockers, ACE-inhibitors, angiotensin II receptors blockers and calcium channel blockers.

Direct and indirect indices of neuroadrenergic function have shown that end-stage renal disease is characterized by a marked sympathetic overdrive. It is unknown, however, whether this phenomenon represents a peculiar feature of end-stage renal disease or whether it is also detectable in the early clinical phases of the disease. The study has been performed in 73 hypertensive patients, of which there were 42 (age: 60.7±1.8 years, mean±SEM) with a stable moderate chronic renal failure (mean estimated glomerular filtration rate: 40.7 mL/min per 1.73 m2, MDRD formula) and 31 age-matched controls with a preserved renal function. Measurements included anthropometric variables, sphygmomanometric and beat-to-beat blood pressure, heart rate (ECG), venous plasma norepinephrine (high-performance liquid chromatography), and efferent postganglionic muscle sympathetic nerve activity (microneurography, peroneal nerve). For similar anthropometric and hemodynamic values, renal failure patients displayed muscle sympathetic nerve activity values significantly and markedly greater than controls (60.0±2.1 versus 45.7±2.0 bursts per 100 heartbeats; P<0.001). Muscle sympathetic nerve activity showed a progressive and significant increase from the first to the fourth quartile of the estimated glomerular filtration rate values (first: 41.0±2.7; second: 51.9±1.7; third: 59.8±3.0; fourth: 61.9±3.3 bursts per 100 heartbeats), the statistical significance (P<0.05) between groups being maintained after adjustment for confounders. In the population as a whole, muscle sympathetic nerve activity was significantly and inversely correlated with the estimated glomerular filtration rate (r=-0.59; P<0.0001). Thus, adrenergic activation is a phenomenon not confined to advanced renal failure but already detectable in the initial phases of the disease. The sympathetic overdrive parallels the severity of the renal failure, state and, thus, it might participate, in conjunction with other factors, at the disease progression.

Resistant hypertension, namely the hypertensive state characterized by the inability of multiple antihypertensive drug interventions to lower blood pressure to goal levels, represents a condition frequently detected in clinical practice. Its main features are represented by its heterogeneous etiology as well as its very high cardiovascular risk. This latter peculiarity has implemented the research for new approaches to the treatment of the disease. This article will focus on two of them, namely carotid baroreceptor electric stimulation and the renal denervation procedure. Clinical studies and large-scale clinical trials are presently ongoing with the aim of defining the long-term efficacy and safety profile of the two interventions.

This paper critically addresses the issue of the "J-curve" paradox--the finding described in studies performed about 30 years ago indicating that treatment-induced systolic blood pressure values below 120 or 125 mm Hg and diastolic blood pressure values below 75 mm Hg are characterized by an increase, rather than a reduction, in the incidence of coronary events. This paper focuses on four major subjects: 1) the benefits of a lower blood pressure target during treatment; 2) the historical background of the "J-curve" phenomenon; 3) the evidence collected in recent clinical trials regarding the existence of a "J-curve" in treated hypertensive patients; and 4) the recent recommendations by the Task Force Committee of the European Society of Hypertension on blood pressure goals to be achieved during treatment.

Data collected in experimental animals and in humans support the hypothesis that sympathetic neural mechanisms are involved in the development and progression of hypertension. Direct approaches to assess human adrenergic cardiovascular drive have shown that sympathetic activation occurs in hypertensive patients, the magnitude of which is proportional to the degree of elevation of the blood pressure. Evidence has also been obtained that sympathetic activation participates in the development of hypertension-related target organ damage, such as left ventricular diastolic dysfunction, left ventricular hypertrophy and arterial remodelling and hypertrophy. Despite the large amount of information collected on the main features of the hypertension-related neurogenic abnormality, the causes of the sympathetic activation remain undefined, although alterations in the reflex modulation of adrenergic drive and/or participation of metabolic factors are likely candidates. This paper will provide background information on the behaviour of the sympathetic nervous system in experimental hypertension, followed by a review of the main features, mechanisms and effects of the sympathetic overdrive in human hypertension. Finally, the new frontiers of research in the area of therapeutic intervention aimed at reducing the adrenergic overdrive will be highlighted.

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.

Blood pressure control is the cornerstone of therapeutic interventions aimed at preventing first strokes and recurrent strokes. All antihypertensive drug classes may be useful in preventing cerebrovascular events, depending on their efficacy in lowering elevated blood pressure values and achieving blood pressure control. However, recent findings indicate that drugs acting on the renin-angiotensin system (-angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) may exert cerebrovascular protective effects in addition to blood pressure reduction. This article examines the cerebrovascular protection provided by antihypertensive drug treatment in the light of the results of recent meta-analyses and of the findings of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

It is debated whether white-coat (WCHT) and masked hypertension (MHT) are at greater risk of developing a sustained hypertensive state (SHT). In 1412 subjects of the Pressioni Arteriose Monitorate e Loro Associazioni Study, we measured office blood pressure (BP), 24-hour ambulatory BP, and home BP. The condition of WCHT was identified as office BP >140/90 mm Hg and 24-hour BP mean <125/79 mm Hg or home BP <132/82 mm Hg. Corresponding values for MHT diagnosis were office BP <140/90 mm Hg, 24-hour BP > or =125/79 mm Hg, and home BP >or =132/82 mm Hg. SHT was identified when both office and 24-hour BP means or home BP were over threshold values and normotension was under the threshold value. Subjects were reassessed 10 years later to evaluate the BP status of the various conditions defined previously. At the first examination, 758 (54.1%), 225 (16.1%), 124 (8.9%), and 293 (20.9%) subjects were normotensive, WCHT, MHT, and SHT subjects, respectively. At the second examination, 136 normotensives (18.2%), 95 WCHT (42.6%), and 56 MHT (47.1%) subjects became SHT. As compared with normotensives, adjusting for age and sex, the risk of becoming SHT was significantly higher for WCHT and MHT subjects (odds ratio: 2.51 and 1.78, respectively; P<0.0001). Similar results were obtained when the definition of the various conditions was based on home BP. Independent contributors of worsening of hypertension status were not only baseline BP, but also, although to a lesser extent, metabolic variables and age. Subjects with WCHT and MHT are at increased risk of developing SHT. This may contribute to their prognosis that appears to be worse as compared with that of normotensive subjects.

Objective: A sustained blood pressure elevation is associated with an increased risk of new-onset diabetes mellitus. Whether this is the case also in white-coat and masked hypertension is unknown., Methods: In 1412 individuals of the Pressioni Arteriose Monitorate E Loro Associazioni study stratified for sex and age decades, we measured office, home and 24-h ambulatory blood pressure together with fasting plasma glucose and other metabolic variables. This allowed to identify patients with white-coat, masked, sustained hypertension and true normotension., Results: Over a 10-year period, the increase in plasma glucose and the incidence of new-onset diabetes (plasma glucose > or =126 mg/dl or use of antidiabetic drugs) was significantly greater in individuals with white-coat and masked hypertension than in those with 'true' normotension (age and sex-adjusted risk 2.9 and 2.7, respectively), the increase being similar to that of sustained hypertensive individuals. The adjusted risk showed a marked increase when development of an impaired fasting glucose condition was also considered, and the results were similar when individuals reporting antihypertensive drug treatment were excluded or white-coat and masked hypertension were identified by office versus home blood pressure. The increased risk of new-onset diabetes become no more significant when data were adjusted for initial blood glucose and BMI, which, at a multivariate analysis, were the most significant predictors of this condition, with only a small although significant contribution of the initial blood pressure., Conclusion: Thus, white-coat and masked hypertension are associated with a long-term greater progression of blood glucose abnormalities and an increased risk of developing diabetes. This is largely accounted for by the metabolic abnormalities that are frequent components of these conditions.

Alterations in glucose and lipid metabolism frequently cluster with overweight, obesity as well as hypertension in the clinical condition known as metabolic syndrome. The "cardiometabolic clustering" is characterized by well-known alterations that increase cardiovascular risk profile such as insulin-resistance, endothelial dysfunction, arterial stiffening, cardiac hypertrophy, and sympathetic activation. The present article will review the evidence collected throughout by years that an increase in the different markers of adrenergic drive, such as plasma norepinephrine and muscle sympathetic nerve traffic, characterizes this condition. Frequently, the increase also involves heart rate, as documented by the results of different epidemiological studies, such as the Pressioni Arteriose Monitorate E Loro Associazioni, in which an increase in heart rate has been shown in patients with metabolic syndrome, in which this hemodynamic parameter has been assessed in the doctor's office, at home, or during the 24-hour period. Finally, current findings suggest that in metabolic syndrome heart rate displays a significant correlation with other indirect and direct adrenergic markers. Taken together, these findings reinforce the concept that drugs used in the metabolic syndrome should exert sympathoinhibitory effects.

The sympathetic overdrive that characterizes essential hypertension is potentiated when left ventricular hypertrophy or congestive heart failure is detected. No information exists, however, on whether this is the case also for left ventricular diastolic dysfunction. In 17 untreated hypertensive subjects with left ventricular diastolic dysfunction (age: 47.7+/-2.9 years, mean+/-SEM), we measured sympathetic nerve traffic (microneurography), heart rate (ECG), and beat-to-beat arterial blood pressure (Finapres) at rest and during baroreceptor deactivation and stimulation. Data were compared with those collected in 20 age-matched normotensive and 20 hypertensive subjects without a diastolic function impairment. Muscle sympathetic nerve traffic values were markedly and significantly greater in the 2 hypertensive groups than in the normotensive one (55.3+/-1.2 and 71.2+/-1.6 versus 41.7+/-1.0 bursts per 100 heartbeats, respectively; P<0.01 for both). For a similar blood pressure elevation, however, the sympathetic nerve traffic increase was significantly greater in patients with than without left ventricular diastolic dysfunction (+28.9%; P<0.05). In the population as a whole, muscle sympathetic nerve traffic was significantly and inversely related to various echocardiographic indices of diastolic function. Although baroreflex-heart rate control was significantly attenuated in the 2 hypertensive groups, baroreflex-sympathetic modulation was impaired only in those with diastolic dysfunction. These data provide the first evidence that, in hypertension, activation of the sympathetic nervous system may contribute not only at the blood pressure elevation but also at the development of left ventricular diastolic dysfunction. The sympathetic overactivity, which is likely to be related to the baroreflex impairment, may account for the increased cardiovascular risk characterizing diastolic dysfunction.

Limited information is available on whether and to what extent the different patterns of the nocturnal blood pressure profile reported in hypertension are characterized by differences in sympathetic drive that may relate to, and account for, the different day-night blood pressure changes. In 34 untreated middle-aged essential hypertensive dippers, 17 extreme dippers, 18 nondippers, and 10 reverse dippers, we assessed muscle sympathetic nerve traffic, heart rate, and beat-to-beat arterial blood pressure at rest and during baroreceptor deactivation and stimulation. Measurements were also performed in 17 age-matched dipper normotensives. All patients displayed reproducible blood pressure patterns at 2 different monitoring sessions. The 4 hypertensive groups did not differ by gender or 24-hour or daytime blood pressure. Muscle sympathetic nerve traffic was significantly higher in nondipper, dipper, and extreme dipper hypertensives than in normotensive controls (58.6+/-1.8, 55.6+/-0.9, and 53.3+/-0.8 versus 43.5+/-1.4 bursts/100 heartbeats, respectively; P<0.01 for all), a further significant increase being detected in reverse dippers (76.8+/-3.1 bursts/100 heartbeats; P<0.05). Compared with normotensives, baroreflex-heart rate control was similarly impaired in all the 4 hypertensive states, whereas baroreflex-sympathetic control was preserved. The day-night blood pressure difference correlated inversely with sympathetic nerve traffic (r=-0.76; P<0.0001) and homeostasis model assessment index (r=-0.32; P<0.005). Thus, the reverse dipping state is characterized by a sympathetic activation greater for magnitude than that seen in the other conditions displaying abnormalities in nighttime blood pressure pattern. The present data suggest that in hypertension, sympathetic activation represents a mechanism potentially responsible for the day-night blood pressure difference.

Objectives: Plasma norepinephrine displays a limited ability to reflect the enhanced sympathetic drive characterizing essential hypertension. Among the factors responsible, an important one is the reduced reproducibility of the norepinephrine approach. The present study aimed to determine whether increasing the number of blood samples on which norepinephrine assay is based improves norepinephrine reproducibility. This was done by taking muscle sympathetic nerve traffic recording as 'gold standard', which is characterized by an elevated short- and long-term reproducibility., Methods: In 14 untreated mild-to-moderate essential hypertensive patients, we evaluated, in two experimental sessions spaced each other by a 10-14-day interval, blood pressure (Finapres), heart rate (ECG), plasma norepinephrine (HPLC) and muscle sympathetic nerve traffic (microneurography, peroneal nerve). In the two sessions, three norepinephrine samples were obtained at 30-min intervals between each. Norepinephrine reproducibility between sessions was assessed on a single norepinephrine sample or averaging together the values obtained from second or third samples. Reproducibility of norepinephrine data was then compared with the microneurographic one., Results: Although muscle sympathetic nerve traffic values showed a highly significant correlation between sessions (r=0.79, P<0.001), norepinephrine values derived from a single blood sample did not correlate with each other (r=0.42, P=NS). Norepinephrine correlation coefficients were consistently improved and achieved statistical significance when average data from second or third blood samples were examined (r=0.63, P<0.03)., Conclusion: In essential hypertension, the reproducibility of plasma norepinephrine as an adrenergic marker can be substantially improved by performing a norepinephrine assay on multiple blood samples.

The development of angiotensin II receptor blockers (ARB) as a new class of drugs for the management of hypertension has elicited the attention of many clinicians worldwide with the aim of improving blood pressure (BP) control as well as cardiovascular protection. Among ARB telmisartan has been shown to be characterised by an antihypertensive efficacy fully covering the 24-hour period, thereby allowing to antagonise the adverse effects of early morning BP rise on cardiovascular risk. Other specific effects of the drug are represented by its favourable metabolic profile (particularly on insulin sensitivity) and neutral effects on sympathetic cardiovascular function. These properties are coupled with cardioprotective effects, documented by the evidence that the drug: 1) is effective in favouring the regression of cardiac and vascular organ damage, 2) reduces arterial stiffness and improves vascular distensibility and 3) reverses the endothelial dysfunction typical of the hypertensive state particularly when complicated by renal failure, diabetes, obesity or metabolic syndrome. Several of these properties can account for the results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), documenting the beneficial effects on the drug on cardiovascular morbidity and mortality.

Obesity-related hypertension represents a common clinical condition characterised by complex pathophysiological and therapeutic features. From a pathophysiological view point, results of experimental and animal studies have led to the hypothesis that neurogenic mechanisms participate in the development and progression of the disease. The hypothesis is based on the evidence that metabolic (i.e. insulin-resistance) and neural (sympathetic activation) alterations frequently co-exist in the obese hypertensive patient and that they reciprocally potentiate each other. From a therapeutic view point, the 2007 European Society of Hypertension/European Society of Cardiology emphasised the importance in this clinical condition of treatment not only through antihypertensive drugs but also via lifestyle changes and drug-induced interventions that reduce body weight. The four Rimonabant In Obesity (RIO) studies have shown that rimonabant can decrease body weight. A recent meta-analysis, based on the RIO results, showed that rimonabant, particularly in obese hypertensive patients, can also decrease - although modestly (2.8 mmHg for systolic and 2.2 mmHg for diastolic) - blood pressure. These effects, which appear to be triggered by the weight reduction induced by the drug, are clinically relevant because they contribute favourably to lower the elevated cardiovascular risk profile of the obese hypertensive patient.

Sympathetic neural factors exert a key role in homeostatic blood pressure control. Evidence is available that abnormalities in sympathetic function may favour the development and progression of the hypertensive state. This paper will review the data collected throughout the years on the role of adrenergic mechanisms in the pathophysiology of the hypertensive state. It will then examine the mechanisms and the consequences of the sympathetic overdrive reported in hypertension, with particular emphasis on its role in the development of target organ damage. Finally the therapeutic implications of hypertension-related neurogenic abnormalities will be highlighted.

Background: Blood pressure, as well as blood volume homeostasis, depends to a large extent on humoral influences stemming from the renin-angiotensin axis and the sympathetic nervous system. Evidence has been provided that a large part of this homeostatic modulation is effected by the complex interactions between the two systems., Objectives: The present review will focus on three major issues. First it will examine the physiological and pathophysiological relevance of angiotensin-sympathetic crosstalk discussing possible sites, mechanisms and effects of the interaction. It will then address the clinical relevance of these inter-relationships by reviewing data collected in cardiovascular and non-cardiovascular diseases. Finally, the influences of angiotensin II on adrenergic function will be examined as possible targets of cardiovascular drug treatment., Conclusions: By interrupting the influences of angiotensin II on sympathetic function, therapeutic interventions aimed at blocking the renin-angiotensin system exert favourable effects on the haemodynamic, metabolic and renal profile. This has important implications for the treatment of hypertension, congestive heart failure, renal insufficiency and metabolic syndrome.

Objectives: Vascular remodelling and hypertrophy represent early therapeutic targets of antihypertensive treatment. The present study was aimed at assessing the effects of 1-year administration of the highly vasoselective calcium-channel blocker lercanidipine (10 mg/day) or the diuretic compound hydrochlorothiazide (25 mg/day) on hypertension-related vascular alterations. The study was also aimed at assessing whether and to what extent: (i) pharmacological regression of vascular hypertrophy is related only to the blood pressure (BP) reduction "per se" or also to the specific ancillary properties of a given drug and (ii) treatment provides restoration of vascular function indicative of normal vascular structure., Design and Methods: In 26 untreated patients with mild-to-moderate essential hypertension sphygmomanometric and finger BP, heart rate, forearm and calf blood flow (venous occlusion plethysmography) and corresponding vascular resistance (forearm and calf vascular resistance: FVR and CVR) were assessed before and following 6 and 12 months of either lercanidipine or hydrochlorothiazide administration. Vascular resistance was also evaluated following a local ischaemic stimulus (FVR(min) and CVR(min)) in order to assess the effects of treatment on arteriolar structural alterations., Results: For superimposable BP reductions, lercanidipine caused FVR and CVR to decrease significantly more than hydrochlorothiazide. Similarly, the FVR(min) and CVR(min) reductions induced by lercanidipine were markedly and significantly greater than those caused by hydrochlorothiazide (-46.1% and -40.9% vs -22.5% and -19.9%, p < 0.01 for both). FVR(min), and CVR(min), however, remained higher than those found in 10 age-matched normotensive individuals., Conclusions: These data provide evidence that, compared to hydrochlorothiazide, lercanidipine favours a greater regression of the vascular structural changes associated with hypertension, probably through its "ancillary" properties. Lercanidipine, however, does not allow restoration of a "normal" vascular structure, thereby suggesting that vascular hypertrophy is only in part a reversible phenomenon.

Previous studies have shown that congestive heart failure is characterized by sympathetic and reflex dysfunctions. Whether these alterations are potentiated in the presence of obesity and hypertension, two conditions that also display neuroadrenergic abnormalities and markedly increase the risk of heart failure, is unknown. In 14 healthy control subjects (C; age, 55.1+/-3.0 years; mean+/-SEM), 13 lean hypertensive subjects (H), 15 obese normotensive subjects (O), 14 lean normotensive subjects with congestive heart failure (CHF, New York Heart Association class II), 14 lean hypertensive subjects with CHF (CHFH), 14 obese normotensive subjects with CHF (CHFO), and 13 obese hypertensive subjects with CHF (CHFOH), all age-matched with C, we measured mean blood pressure (Finapres), heart rate (ECG), and muscle sympathetic nerve traffic (MSNA, microneurography) at rest and during baroreflex testing. Compared with C, body mass index was similarly increased in O, CHFO, and CHFOH, whereas mean blood pressure was similarly increased in HF, CHFH, and CHFOH, and left ventricular ejection fraction (echocardiography) was similarly reduced in CHF, CHFH, CHFO and CHFOH. Compared with C, MSNA was significantly increased in O, H, and CHF (43.0+/-2.2 versus 54.1+/-2.8, 53.1+/-2.5, and 57.4+/-2.8 bursts/100 heart beats, P<0.01). When O or H was combined with CHF, the MSNA increase was significantly more pronounced and maximal when O and H were concomitantly associated with CHF. Baroreflex sensitivity was reduced in O and H, with a further reduction in CHF and a minimal value in CHFOH. These data show that the sympathetic activation characterizing CHF is markedly potentiated when O and H alone or combined together are associated with a low cardiac output state and that this may depend on an arterial baroreflex impairment.