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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 P 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.

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±0.4mmHg vs 3 cups/day: 120.2±0.4/74.8±0.3mmHg, PNS) or home BP monitoring (0 cup/day: 124.1±1.2/75.4±0.7mmHg vs 3 cups/day: 123.3±0.6/76.4±0.36mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2mmHg), suggesting some pressor effects of coffee which vanish during nighttime. Both BP and HR 24-hour HR variability were unaffected. Conclusion: Thus chronic coffee consumption does not appear to have any major lowering effect either on absolute BP values, particulary when they are assessed via 24-hour ambulatory or home BP monitoring, or on 24-hour BP variability.

Purpose Renal denervation (RDN) exerts sympathoinhibitory effects. No information is available, however, on whether these effects have a regional or a more generalized behavior. Methods In 14 patients with resistant hypertension (RHT, age 58.3 ± 2.2 years, mean ± SEM), we recorded muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively) using the microneurographic technique, before, 1 month, and 3 months after RDN. Measurements included clinic blood pressure (BP), heart rate (HR), 24-h BP and HR, as well as routine laboratory and echocardiographic variables. Ten age-matched RHT patients who did not undergo RDN served as controls. Results MSNA, but not SSNA, was markedly higher in RHT. RDN caused a significant reduction in MSNA 1 month after RDN, with this reduction increasing after 3 months (from 68.1 ± 2.5 to 64.8 ± 2.4 and 63.1 ± 2.6 bursts/100 heartbeats, P 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.

Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly ( P r =0.51, P r =0.47, P r =0.76, P r =0.46, P

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.

BACKGROUND Microneurographic recordings of muscle sympathetic nerve activity (MSNA) have shown that sympathetic activation may characterize diabetes mellitus. However, it is recognized that comorbidities and metabolic abnormalities frequently associated with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) diabetes affect MSNA, generating potential confounding effects and making the association between sympathetic activation and diabetes mellitus still a controversial matter. METHODS The present meta-analysis evaluated 11 microneurographic studies enrolling 314 diabetes mellitus patients and healthy controls, and MSNA was chosen as the main variable of interest. Collection of the data included indirect adrenergic markers such as heart rate and venous plasma noradrenaline, together with hemodynamic, anthropometric and metabolic variables. RESULTS A total of 11 microneurographic studies were evaluated including 314 diabetes mellitus patients and controls. Diabetes mellitus displayed MSNA significantly greater than controls (mean difference amounting to 8.1, 95% confidence interval 1.21-15.08, P

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.

Background and aim: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. Methods and results: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA

Objective: Whether and to what extent the reported BP lowering effects of renal denervation (RD) are mediated by a sympathetic deactivation induced by the procedure is still largely undefined. We examined this issue by performing a meta-analysis of the microneurographic studies published so far based on the evaluation of the blood pressure (BP) and muscle sympathetic nerve traffic (MSNA) responses to RD. Design and method: The meta-analysis was based on 12 studies including a total of 394 patients with resistant hypertension underwent RD and followed up to 12 months. Evaluation was extended to the relationships of MSNA with heart rate (HR) and clinic or ambulatory blood pressure (BP) values (expressed such as mean and 95% confidence interval). Results: Baseline MSNA values amounted to 48.25 (43.86-52.64) bursts/minute, clinic HR to 66.35 (65.02-67.67) beats/minute and systo/diastolic clinic BP to 167.3 (157.6-177.01) and 90.54 (84.81-96.27) mmHg. RD caused a significant BP reduction at 3/6/12 months following the procedure amounting to 12.6 mmHg for systolic (range 20.9 to 4.39 mmhg, p = 0.003) and to 6.4 mmHg for diastolic BP (range -11.9 t0 0.9 mmHg, p = 0.02) respectively. No significant change in MSNA (-2.65, range -6.7 to 1.4 bursts/minute, P = NS) and HR (-0.58, range -3.98 to 2.81 b/min, P = NS) were concomitantly observed. No relationship was found between the number of renal ablations and the magnitude of the blood pressure or MSNA changes, this being the case also for HR. Conclusions: This meta-analysis, the first ever done on the MSNA responses to RD, shows that in a consistent number of patients underwent RD, the BP lowering effects of the procedure are not accompanied by any significant change in 2 adrenergic markers, i.e. MSNA and HR, and thus appear not to be mediated by any sympathetic deactivation.

BACKGROUND Neuroadrenegic overdrive occurs in obstructive sleep apnoea syndrome (OSAS). However, the small sample size of the microneurographic studies, heterogeneity of the patients examined, presence of comorbidities, represented major weaknesses not allowing to precisely define the main features of the phenomenon, particularly in nonobese patients. OBJECTIVE This meta-analysis detected 14 microneurographic studies based on muscle sympathetic nerve activity (MSNA) quantification in uncomplicated OSAS of different clinical severity. METHODS The evaluation was extended to the relationships of MSNA with heart rate, anthropometric and blood pressure values, metabolic variables, apnoea-hypopnea index and oxygen saturation. RESULTS MSNA is activated markedly and almost homogeneously between studies, showing a progressive increase from the healthy state to mild, moderate and severe OSAS (46.03, 48.32, 71.84, 69.27 bursts/100 heart beats). Of special interest are the findings that MSNA is significantly related to the apnoea-hypopnea index, a marker of OSAS severity (r = 0.55, P = 0.04) but not to BMI, as it occurs in OSAS associated with obesity, and heart rate is significantly and directly related to MSNA and apnoea-hypopnea index (r = 0.68 and r = 0.60, respectively P = 0.03 and P = 0.02), thus representing a surrogate marker of the sympathetic overdrive. CONCLUSION OSAS, even when uncomplicated by other cardiometabolic disease, displays a marked sympathetic activation, reflected by the MSNA and heart rate behaviour, becoming a target of therapeutic interventions aimed at exerting sympathomoderating effects, such as continuous positive airway pressure.

Background: Scarce and non-homogeneous data are available on the prognostic value of clinic heart rate (HR) in coronavirus disease 2019 (COVID-19). Methods: The present study evaluated in 389 patients hospitalized for COVID-19 the in-hospital prognostic value of resting HR, assessed over different time periods, i.e., at hospital admission, during initial 3 days and 7 days of hospitalization. Results: Results show that assessment of this hemodynamic variable during hospitalization provides information on the clinical outcome of the patients, greater HR values being associated with a worse in-hospital prognosis. The prognostic value of elevated HR during COVID-19: 1) was independent on other confounders such as age, gender, comorbidities and fever, 2) appeared to be strengthened by repeated measurements of HR during the initial 3/7 days of hospitalization, and 3) was detectable in patients in which the therapeutic intervention did not include drugs, such as beta-blockers, calcium antagonists, digoxin, ivabradine and antiarrhythmic compounds known to interfere with HR. Conclusions: Heart rate may represent an important marker of a patient’s outcome in COVID-19.

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

Objective: No trial-based evidence is available on whether antihypertensive treatment lowers cardiovascular risk in white-coat hypertension (WCH). Protection may be indirectly inferred, however, from the blood pressure (BP) effects of treatment, because in trials outcomes decrease is linearly related to BP reduction. We andomis the effect of antihypertensive treatment on office and out-of-office BP in WCH using data from the Plaque HYpertension Lipid-Lowering Italian Study (PHYLLIS). Design and method: Office and ambulatory BP were measured in 470 hypertensive patients andomisat to an ACE-inhibitor or a diuretic alone or combined with a statin before treatment and at yearly intervals during a 3-year follow-up. Patients were divided into two groups according to whether baseline data obtained before andomisation to treatment showed that 1) office and 24-hour mean BP were elevated (75.8% sustained hypertensive, SH) or 2) office BP was elevated but 24-hour BP values were normal (24.2% WCH). Results: Antihypertensive drug treatment was associated with an early marked reduction of BP, which persisted virtually unchanged throughout the treatment period and was only slightly and usually not significant different in SH and WCH (-18.9 ± 11.1/-12.7 ± 5.9 mmHg for SBP/DBP in SH and -18 ± 10.4/-12.3 ± 6.2 for SBP/DBP in WCH p = 0.43/p = 0.52). This was not the case, however, for 24-h BP which, fell consistently in SH while showing no change in WCH(-10.7 ± 10.8/1.0 ± 8.3 mmHg for SBP/DBP in SH and -7.4 ± 7.2/0.1 ± 4.8 for SBP/DBP in WCH p < 0.001/p < 0.001). In SH but not in WCH antihypertensive treatment consistently reduced either the higher daytime and the lower nighttime SBP and DBP values during the treatment. Conclusions: 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.

INTRODUCTION 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 an unique research for a number of reasons. EVIDENCE ACQUISITION AND SYNTHESIS The PAMELA study combines clinic, home and 24-hour blood pressure measurements in all partiicipants, which were representative of the general population. Examination included metabolic variables, allowing us to determine the interrelationships between bood 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 actually under analysis. This will allow to update the information related to cardiovascular morbidity and mortality in the study cohort. CONCLUSIONS The present paper will provide 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.

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

Masked hypertension (MH) is defined as normal office blood pressure (BP) and elevated ambulatory BP (ABP) or home BP or both. This study assessed the association of MH (ie, isolated home, isolated ABP and dual MH) with echocardiographic left ventricular hypertrophy (LVH). The present analysis of the PAMELA study included 1087 untreated and treated participants with normal office BP and a measurable LV mass (LVM). A total of 193 individuals (17.7%) had any MH (ie, normal office BP, elevated ABP or home BP or both), 48 had dual MH (25%), 62 isolated ambulatory MH (32%), and 83 isolated home MH (43%). Average LVM indexed to body surface area was superimposable in the three MH phenotypes (being the largest difference between groups

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 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 r =0.34–0.36, P

BACKGROUND AND OBJECTIVES Sympathetic neural activation occurs in congestive heart failure (CHF). However, the small sample size of the microneurographic studies, heterogeneity of the patients examined, presence of comorbidities as well as confounders (including treatment) represented major weaknesses not allowing to identify the major features of the phoenomenon, particularly in mild CHF. This meta-analysis evaluated 2530 heart failure (CHF) patients recruited in 106 microneurographic studies. It was based on muscle sympathetic nerve activity (MSNA) quantification in CHF of different clinical severity, but data from less widely addressed conditions, such as ischemic vs. idiopathic, were also considered. METHODS Assessment was extended to the relationships of MSNA with venous plasma norepinephrine, heart rate (HR) and echocardiographic parameters of cardiac morphology [left ventricular (LV) end-diastolic diameter] and function (LV ejection fraction) as well. RESULTS MSNA was significantly greater (1.9 times, P

Nerve traffic recordings (muscle sympathetic nerve traffic [MSNA]) have shown that sympathetic activation may occur in obesity. However, the small sample size of the available studies, presence of comorbidities, heterogeneity of the subjects examined represented major weaknesses not allowing to draw definite conclusions. This is the case for the overweight state. The present meta-analysis evaluated 1438 obese or overweight subjects recruited in 45 microneurographic studies. The analysis was primarily based on MSNA quantification in obesity and overweight, excluding as concomitant conditions hypertension, metabolic syndrome, and other comorbidities. Assessment was extended to the relationships of MSNA with other neuroadrenergic markers, such as plasma norepinephrine and heart rate, anthropometric variables, as body mass index, waist-to-hip ratio, presence/absence of obstructive sleep apnea, and metabolic profile. Compared with normoweights MSNA was significantly greater in overweight and more in obese individuals (37.0±4.1 versus 43.2±3.5 and 50.4±5.0 burts/100 heartbeats, P r =0.41 and r =0.64, P r =0.68, P r =0.91, r =0.94, and r =0.80, respectively, P

Heart rate is a parameter that is very easy to measure and is widely used both in clinic and during daily life activities. Its value gained more relevance with the evidence, in prospective studies and meta-analysis, of association between elevated heart rate values and diseases and outcomes.The increased knowledge of physiological mechanisms of heart rate control and the pathophysiological mechanisms responsible for its dysfunction allows to identify the cut-off value of normalcy providing info for non-pharmacological and pharmacological treatments to reduce the cardiovascular risk both in general population and in pathophysiological conditions. This paper overviews the knowledges of the role of resting heart rate as predictor of cardiovascular risk.

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. Summary 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.

Purpose The present paper will review the impact of different therapeutic interventions on the autonomic dysfunction characterizing chronic renal failure. Methods We reviewed the results of the studies carried out in the last few years examining the effects of standard pharmacologic treatment, hemodialysis, kidney transplantation, renal nerve ablation and carotid baroreceptor stimulation on parasympathetic and sympathetic control of the cardiovascular system in patients with renal failure. Results Drugs acting on the renin–angiotensin system as well as central sympatholytic agents have been documented to improve autonomic cardiovascular control. This has also been shown for hemodialysis, although with more heterogeneous results related to the type of dialytic procedure adopted. Kidney transplantation, in contrast, particularly when performed together with the surgical removal of the native diseased kidneys, has been shown to cause profound sympathoinhibitory effects. Finally, a small amount of promising data are available on the potential favorable autonomic effects (particularly the sympathetic ones) of renal nerve ablation and carotid baroreceptor stimulation in chronic kidney disease. Conclusions Further studies are needed to clarify several aspects of the autonomic responses to therapeutic interventions in chronic renal disease. These include (1) the potential to normalize sympathetic activity in uremic patients by the various therapeutic approaches and (2) the definition of the degree of sympathetic deactivation to be achieved during treatment.

Background: Chronic kidney disease (CKD) is characterized by a pronounced sympathetic overactivity as documented by the marked increase in muscle sympathetic nerve traffic (MSNA) and in plasma norepinephrine reported in this condition. Whether and to what extent in CKD heart rate (HR) reflects the adrenergic overdrive remains undefined. It is also undefined the relative validity of the different adrenergic markers in reflecting renal dysfunction. Materials and methods: In 82 CKD patients, aged 58.4 ± 1.1 years (mean ± SEM), we measured resting clinic blood pressure, HR (EKG), venous NE (HPLC) and MSNA (microneurography). The same measurements were made in 24 age-matched healthy controls. Results: HR was significantly greater in CKD than in controls (74.0 ± 1.1 versus 68.2 ± 1.8 bpm, P < 0.02) and significantly directly related to the elevated plasma norepinephrine and MSNA values (r = 0.22 and 0.39, P < 0.05 and

In 1722 hypertensives recruited for the European Lacidipine Study on Atherosclerosis and treated with atenolol or lacidipine (±additional drugs) during 4 years, we evaluated the long-term reproducibility of dipping, nondipping, extreme dipping, and reverse dipping, an information of key relevance for defining the prognostic impact of these blood pressure (BP) phenotypes. Ambulatory BP was measured at baseline and every year during treatment, allowing repeated classifications of these conditions. Based on systolic BP, at baseline 50.1%, 37.5 %, 4.5 %, and 7.9 % were dippers, nondippers, extreme dippers, and reverse dippers, respectively. Antihypertensive drug treatment reduced the number of dippers and extreme dippers in favor of nondippers and reverse dippers. During treatment, the dipping and nondipping phenotypes were markedly unstable and shifts from one to other phenotypes were even more common in reverse and extreme dippers In only a very small fraction of patients, a given nighttime BP phenotype was persistently found throughout the 4 years. Data were similar for diastolic BP and in subgroups differing for the type of treatment, the treatment complexity, and the achieved on-treatment BP value Poor reproducibility characterized also the absolute nighttime BP reduction as measured by the nighttime BP fall and the night/day BP ratio. Thus nighttime BP phenotypes are all largely inconsistent, their detection over the entire treatment period involving just a minute fraction of the entire patients’ cohort.

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

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&nbsp

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.

Objectives: In older individuals, the role of serum uric acid (SUA) as risk factor for mortality is debated. This study investigated the association of SUA with all-cause and cardiovascular (CV) mortality in older adults participating in the large multicentre observational uric acid right for heart health (URRAH) study. Methods: Eight thousand URRAH participants aged 65+ were included in the analysis. The predictive role of SUA was assessed using Cox regression models stratified according to the cut-off age of 75. SUA was tested as continuous and categorical variable (age-specific quartiles). The prognostic threshold of SUA for mortality was analysed using receiver operating characteristic curves. Results: Among participants aged 65-74, multivariate Cox regression analysis adjusted for CV risk factors and comorbidities identified an independent association of SUA with both all-cause mortality (hazard ratio [HR] 1.169, 95% confidence interval [CI] 1.107-1.235) and CV mortality (HR 1.146, 95% CI 1.064-1.235). The cut-off value of 4.8 mg/dl discriminated mortality status. In participants aged 75+, we observed a J-shaped relationship of SUA with all-cause and CV mortality, with risk increasing at extreme SUA levels. Conclusions: These results confirmed the predictive role of SUA for all-cause and CV mortality in older adults, while revealing considerable age-related differences. Mortality risk increased at higher SUA levels in participants aged 65-74, with a prognostic threshold of 4.8 mg/dl. The relationship between SUA and mortality was J-shaped in oldest participants. Large interventional studies are needed to clarify the benefits and possible risks of urate-lowering treatments in older adults.

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

BACKGROUND: Neuroadrenergic overdrive occurs in obstructive sleep apnea syndrome (OSAS). However, the small sample size of the microneurographic studies, heterogeneity of the patients examined, presence of comorbidities, represented major weaknesses not allowing to precisely define the main features of the phenomenon, particularly in nonobese patients. OBJECTIVE: This meta-analysis evaluated 850 participants recruited in 26 microneurographic studies, based on muscle sympathetic nerve activity (MSNA) quantification in uncomplicated OSAS of different clinical severity. METHODS: The evaluation was extended to the relationships of MSNA with heart rate (HR), anthropometric and blood pressure (BP) values, metabolic variables, apnea-hypopnea index (AHI) and oxygen saturation. RESULTS: MSNA is activated markedly and almost homogeneously between studies, showing a progressive increase from the healthy state to mild, moderate and severe OSAS (41.6, 48.3, 65.5 and 70.7 bursts/100 heart beats, respectively, P

Whether blood pressure (BP) values differ when BP is measured with or without the presence of a doctor (attended and unattended BP measurements) is controversial, and no information exists on whether and to what extent neurogenic mechanisms participate at the possible BP differences between these measurements. In this study, we assessed continuous beat-to-beat finger systolic BP and diastolic BP, heart rate, muscle, and skin sympathetic nerve traffic (microneurography) before and during BP measurement by an automatic device in the presence or absence of a doctor. This was done in 18 untreated mild-to-moderate essential hypertensive patients (age, 40.2±2.8 years, mean±SEM). During attended BP measurement, there was an increase in systolic BP, diastolic BP, heart rate, and skin sympathetic nerve traffic and a muscle sympathetic nerve traffic decrease, the peak changes being +5.3%,+8.4%,+9.4%,+30.9%, and −15.2%, respectively ( P

The recent European Society of Cardiology/European Society of Hypertension hypertension guidelines identify resting heart rate (HR) values >80 bpm as predictors of cardiovascular risk, with the unproven assumption that this might reflect the presence of a sympathetic overdrive. In the present study, we tested this hypothesis throughout the use of direct and indirect sympathetic markers. In 193 untreated moderate essential hypertensives aged 50.4±0.6 years (mean±SEM), we measured clinic and ambulatory blood pressure and corresponding HR, venous plasma norepinephrine (high performance liquid chromatography), and muscle sympathetic nerve traffic (microneurography). We then subdivided the study population into 2 groups according to HR < or >80 bpm. Eighty-four patients displayed resting HR >80 bpm, which was this cutoff value in the remaining 109 patients, the 2 groups showing superimposable age, and sex distribution. Clinic and ambulatory blood pressure were similar in the 2 groups, whereas left ventricular mass index was significantly greater in the group with HR >80 bpm. Muscle sympathetic nerve traffic values were also significantly greater in this latter group (72.77±0.9 versus vs 36.83±1.3 bursts/min, P P 80 bpm are characterized by a marked sympathetic overdrive, particularly when direct adrenergic markers are used. This finding suggests that cardiac and peripheral sympathetic activation are involved in the increased cardiovascular risk detected in this group of patients.

Background: Metabolic syndrome is characterized by a pronounced sympathetic overactivity as documented by the marked increase in muscle sympathetic nerve traffic (MSNA) as well as in plasma norepinephrine values reported in this condition. Whether and to what extent heart rate (HR) reflects the abovementioned adrenergic alterations in metabolic syndrome remains largely undefined. It is also undefined the validity of the abovementioned adrenergic markers in reflecting the main features of the metabolic syndrome. Methods: In 65 metabolic syndrome patients, aged 56.5 ± 1.3 years (mean ± SEM), we measured over a 30-min resting period blood pressure, HR (ECG), venous plasma norepinephrine (HPLC) and MSNA (microneurography). We also evaluated anthropometric and metabolic variables including HOMA index, correlating them with the adrenergic markers. The same measurements were also made in 48 age-matched healthy controls. Results: HR was significantly greater in the metabolic syndrome patients than in controls (74.6 ± 1.5 versus 67.5 ± 1.5 bpm, P < 0.001) and significantly and directly correlated with the elevated norepinephrine and MSNA values (r = 0.25 and 0.33, P < 0.05 and 0.01, respectively). MSNA was significantly and directly related to blood pressure (r = 0.27 and 0.31 SBP and DBP, respectively, P < 0.05 for both), BMI (r = 0.36, P < 0.01), waist circumference (r = 0.34, P < 0.01), waist-to-hip ratio (r = 0.49, P < 0.01) and plasma insulin (r = 0.57, P < 0.01). In contrast, no significant correlation was detectable between HR or norepinephrine and the abovementioned anthropometric and metabolic variables. Conclusion: Our data show that in the metabolic syndrome not only peripheral but also cardiac sympathetic drive is markedly potentiated and HR can be regarded as a marker of adrenergic overdrive characterizing this clinical condition. The reliability of HR (and of plasma norepinephrine) as sympathetic marker appears to be limited, however, this variable being unable to reflect, at variance from MSNA, the main metabolic and anthropometric abnormalities characterizing the metabolic syndrome.

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.