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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: According to some guidelines, white-coat hypertension (WCH) carries little or no increase of cardiovascular risk in the absence of organ damage (OD), but no data are available on this issue., Methods: Using the population data from PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni), we evaluated cardiovascular and total mortality over a median follow-up of 29 years in WCH (elevated office and normal 24-hour or home blood pressure [BP]) and normotensive controls (normal in- and out-of-office blood pressure) with no echocardiographic left ventricular hypertrophy and no reduction of estimated glomerular filtration rate. Patients with sustained hypertension (SH, in- and out-of-office blood pressure elevation) and normotensive, WCH, and SH with cardiac and renal OD served as controls., Results: In the 1423 subjects analyzed, there were 165 cardiovascular and 526 all-cause deaths. After adjustment for confounders, no-OD WCH exhibited a risk of fatal cardiovascular events lower than that of no-OD SH but greater than that of no-ODN (hazard ratio, 2.0 [95% CI, 1.1-3.6], P =0.02), this being the case also for all-cause mortality. Compared with no-OD normotensive, no-OD WCH also exhibited a greater 10-year adjusted risk to develop new SH or OD. Similar findings were obtained in normotensive, WCH, and SH with OD., Conclusions: The present study provides the first evidence that WCH with no OD is accompanied by a noticeable increase in long-term risk of mortality, new hypertension, and new OD, thereby differing from normotension.

Obstructive sleep apnea is a frequent finding in clinical practice especially with the obesity epidemic and the growing awareness of sleep-disordered breathing as a potential and treatable risk factor for cardiovascular diseases. It frequently coexists undiagnosed activating pathophysiological mechanisms known to participate in development and progression of cardiovascular diseases and resistance to therapeutical strategies. The sympathetic activation and the baroreflex and chemoreflex impairment appear to be the main pathophysiological factors that activating several mechanisms elicit cardiac and vascular damage. Data from cross-sectional population-based studies, prospective studies and meta-analysis have clearly shown the implication of OSA in the development of the hypertensive state and the benefits obtained by continuous positive airway pressure on daytime blood pressure and cardiovascular risk., (© 2021. Italian Society of Hypertension.)

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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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.

Home and 24-hour blood pressure (BP Home and BP 24h ) are believed to improve the prognostic value of office BP (BP Office ) alone, but the evidence has limitations such as that (1) these 3 BPs are characterized by multicollinearity and (2) the procedures adopted do not allow quantification of the prognostic advantage. One thousand eight hundred thirty-three individuals belonging to the PAMELA (Pressioni Arteriose Monitorate e Loro Associazioni) were followed for 16 years. Prediction of cardiovascular and all-cause mortality was determined via the goodness of fit of individual data (Cox model), the area underlying the receiving operator curves and the net reclassification improvement of cardiovascular and all-cause mortality risk. Calculations were made for BP Office alone and after addition of BP Home , BP 24h , or both, limited to their residual portion which was found to be unexplained by, and thus independent on, BP Office . With all methods addition of residual out-of-office systolic or diastolic BP to BP Office significantly improved cardiovascular and all-cause mortality prediction. The improvement was more consistent when BP Home rather than BP 24h was added to BP Office and, compared with BP Office plus BP Home , no better prediction was found when addition was extended to BP 24h . With all additions, however, the improvement was quantitatively modest, which was the case also when data were separately analyzed in younger and older individuals or in dippers and nondippers. Thus, addition of out-of-office to BP Office improves prediction of cardiovascular risk, even when data analysis avoids previous limitations. The improvement appears to be limited, however, which raises the question of the advantage to recommend their extended use in clinical practice.

Indirect and direct approaches to assess sympathetic neural function in man have shown that congestive heart failure is characterized by a marked adrenergic overdrive. Although compensatory in the initial phases of the disease, with time the sympathetic overactivity exerts adverse cardiovascular effects, favoring the disease progression and promoting the occurrence of non-fatal and fatal cardiovascular events. This explains why the adrenergic overactivity has become an important target of the therapeutic interventions adopted in the managementof the disease. The present paper will examine the impact of therapeutic approaches, used in the management of heart failure, on the sympathetic activation characterizing the disease. After a brief mention of the sympathetic effects of non-pharmacological interventions and procedural approches, particular emphasis will be given to the effects of pharmacological interventions and device treatments (renal denervation and carotid baroreceptor stimulation), which became in recent years a promising tool for the management of the disease. The clinical implications as well as the unsolved aspects related to the sympathomodulatory interventions in heart failure management will be finally discussed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Purpose of Review: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma., Recent Findings: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.

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.

Purpose of Review: To evaluate the relation between sleep alterations, with or without breathing disorders, and incidence of hypertension and other cardiovascular diseases RECENT FINDINGS: Several studies have clearly shown the mechanisms linking sleep disorders and cardiovascular diseases. The sympathetic hyperactivity seems to play a fundamental role in favoring and sustaining the increase in blood pressure values. Several other mechanisms also contribute to this effect and to the increase cardiovascular risk. The mechanisms responsible for the increase in blood pressure values in subjects with alteration in sleep quantity and quality, with or without breathing disorders, have been clearly established. The recent findings refer to the result of meta-analysis of cross-sectional studies or longitudinal studies showing a significant association between short sleep duration and hypertension. It has also been shown that sleep fragmentation could be considered the main determinant of the sympathetic activation independently of the frequency and severity of oxygen desaturation.

: Obesity is a key factor for cardiovascular diseases and complications. Obesity is associated with hypertension, dyslipidemia and type II diabetes, which are the major predictors of cardiovascular disease in the future. It predisposes for atrial fibrillation, heart failure, sudden cardiac death, renal disease and ischemic stroke that are the main causes of cardiovascular hospitalization and mortality. As obesity and the cardiovascular effects on the vessels and the heart start early in life, even from childhood, it is important for health policies to prevent obesity very early before the disease manifestation emerge. Key roles in the prevention are strategies to increase physical exercise, reduce body weight and to prevent or treat hypertension, lipids disorders and diabetes earlier and efficiently to prevent cardiovascular complications.Epidemiology and mechanisms of obesity-induced hypertension, diabetes and dyslipidemia will be reviewed and the role of lifestyle modification and treatment strategies in obesity will be updated and analyzed. The best treatment options for people with obesity, hypertension, diabetes and dyslipidemia will discussed.

Small-artery remodeling is an early feature of target organ damage in hypertension and retains a negative prognostic value. The aim of the study is to establish age- and sex-specific reference values for media/lumen in small arteries obtained in humans by biopsy. Data from 91 healthy individuals and 200 individuals with cardiovascular risk factors in primary prevention from 4 Italian centers were pooled. Sex-specific equations for media/lumen in the healthy subpopulation, with age as dependent variable, were calculated. These equations were used to calculate predicted media/lumen values in individuals with risk factors and Z scores. The association between classical risk factors and Z scores was then explored by multiple regression analysis. A second-degree polynomial equation model was chosen to obtain sex-specific equations for media/lumen, with age as dependent variable. In the population with risk factors (111 men, age 50.5±14.0 years, hypertension 80.5%), media/lumen Z scores were independently associated with body mass index (standardized β=0.293, P =0.0001), total cholesterol (β=0.191, P =0.031), current smoking (β=0.238, P =0.0005), fasting blood glucose (β=0.204, P =0.003), systolic blood pressure (β=0.233, P =0.023), and female sex (β=0.799, P =0.038). A significant interaction between female sex and total cholesterol was found (β=-0.979, P =0.014). Results were substantially similar in the hypertensive subgroup. A method to calculate individual values of remodeling and growth index based on reference values was also presented. Age- and sex-specific percentiles of media/lumen in a healthy population were estimated. In a predominantly hypertensive population, media/lumen Z scores were associated with major cardiovascular risk factors, including body mass index, cholesterol, smoking, glucose, and systolic blood pressure. Significant sex differences were observed., (© 2018 American Heart Association, Inc.)

Background: Renal denervation reduces blood pressure (BP) and sympathetic drive in experimental animal models, but the effect of this intervention on sympathetic activity in patients with treatment-resistant hypertension is still unclear., Methods: In an incident series of 29 patients with treatment-resistant hypertension, we performed serial measurements (n = 123) of muscle sympathetic nerve activity (MSNA, microneurography) and standardized BP measurements. Data were analysed by mixed linear modelling (MLM) and by regression analysis of time-integrated changes of both MSNA and synchronous, standardized (in-lab) BP measurements., Results: Bilateral renal denervation was accompanied by a marked reduction in MSNA (P = 0.01 by MLM), which was parallelled by a reduction in systolic (from 175 ± 14 to 156 ± 16 mmHg) and, to a lesser extent, in diastolic (from 96 ± 12 to 87 ± 6 mmHg) BP over time. Neither systolic nor diastolic BP associated to a significant extent with corrected MSNA (MSNAC) in the MLM analysis (systolic BP versus MSNAC: β = -0.08, P = 0.08; diastolic BP versus MSNAC: β = -0.007, P = 0.75). However, the study of time-integrated changes in MSNA and BP showed a robust association between proportional changes in MSNA over time and simultaneous changes in systolic and diastolic BP (β = 0.61, P < 0.001 and β = 0.37 P < 0.05)., Conclusions: Time-integrated changes in MSNAC and BP after bilateral renal denervation document a close link between the sympathetic activity and BP responses to this procedure. These findings further strengthen the relevance of the sympathetic nervous system both in the pathophysiology of resistant hypertension and in the BP-lowering effect of the procedure., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Obesity and in particular the excessive visceral fat distribution is accompanied by several alterations at hormonal, inflammatory and endothelial level. These alterations induce a stimulation of several other mechanisms that contribute to the hypertensive state and on the other side to increase the cardiovascular morbidity. In these chapter we will examine the main mechanisms of obesity and obesity-related hypertension and in particular the role of sympathetic nervous system, the alterations of the renal function and at the microvascular level. We will also depict the role of insulin resistance as factor stimulating and potentiating the other mechanisms. The second part will be focalized on the major target organ damage linked with obesity and obesity-related hypertension. We will finally describe the management and treatment of obesity and the antihypertensive drug therapies more effective in hypertensive obeses., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The present study was aimed at comparing the antihypertensive efficacy, tolerability, and side effects profile of nebivolol/hydrochlorothiazide (NH) vs irbesartan/hydrochlorothiazide (IH) combination in elderly patients with isolated systolic hypertension (ISH)., Methods: 124 ISH patients aged 69.1 ± 5.1 years (mean ± SD) were enrolled by 13 general practitioners in Netherlands and Belgium and randomized in a double-blind fashion to receive either NH (5/12.5 mg day, n = 62) or IH (150/12.5 mg day, n = 62) for a 12-week period. The primary efficacy endpoint of the study was the comparison of the two combinations in terms of sitting office systolic blood pressure (BP) reduction after 12 weeks of treatment. In addition ambulatory BP, 24-h BP variability, tolerability, and safety profile were also investigated., Results: 122 patients were included in the intention-to-treat analysis. After 12 weeks of treatment the reduction of systolic BP with NH was significantly greater than IH (-25.8 ± 12 vs -21.2 ± 14 mm Hg, P < 0.03). Diastolic BP reduction was significantly greater with NH after 4 and 8 weeks of treatment but similar at the end of the study (or after 12 weeks). In contrast, the magnitude of the 24-h, daytime, and nighttime systolic and diastolic BP reduction was almost similar in the two groups, while heart rate reduction induced by NH was significantly (P < 0.001) greater during the 24-h, daytime, and nighttime period than that induced by IH. NH caused a reduction in 24-h BP variability significantly greater than IH (standard deviation -4.4 ± 2.7 vs -2.2 ± 5.1 mm Hg, P < 0.02, variation coefficient -2.0 ± 2.6 vs -0.3 ± 3.4%, P < 0.01). Both treatment regimens were well tolerated., Conclusions: These data provide evidence that NH reduces office BP more than IH but has similar effects on 24-h BP. NH reduces 24-h systolic and diastolic BP variability more than IH, suggesting a greater protective effect on a variable known to adversely affect prognosis., Trial Registration: EU clinical Trials Register identifier, 2010-023104-28., Funding: Menarini International Operations Luxembourg.

Experimental and clinical studies have clearly shown the role of the sympathetic nervous system in the pathophysiology of several cardiovascular and non-cardiovascular diseases. This short review will be aimed at focusing and discussing the new information collected on two specific clinical conditions such as obesity and metabolic syndrome. The paper will briefly describe the four main mechanisms that represent the common link between these two pathophysiological conditions and that through the sympathetic nervous system contribute to increase the cardiovascular risk.

Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Introduction and Objective: Blood pressure variability (BPV) within 24 h or between visits has been found to represent an independent risk factor for cardiovascular disease. The present study was aimed at determining whether a clinical significance can be given also to the BP variations occurring within a single clinical visit., Methods: BPV was quantified as coefficient of variation and as standard deviation (SD) of the mean of three systolic SBP values within a visit in the context of a large-cross subclinical survey (BP-CARE) of treated hypertensive patients living in Eastern European countries. The study population was divided into coefficient of variation and SD quartiles and for each quartile a relationship was sought with a large number of cardiovascular risk factors based on patients' history, physical and laboratory examinations., Results: The 6425 hypertensive patients had an age of 59.2 ± 11 years (mean ± SD); they were equally distributed by sex and displayed an average SD and coefficient of variation amounting to 5.1 ± 6.2 mmHg and 3.5 ± 4.0%, respectively. Compared with the lowest coefficient of variation quartile (Q1), patients in the highest quartile (Q4) showed a significantly greater prevalence of several cardiovascular risk factors, such as age (Q1: 58.5 ± 11 vs. Q4: 60.3 ± 11 years, P < 0.001), serum total cholesterol (Q1: 213.0 ± 46 vs. Q4: 216.4 ± 51 mg/dl, P < 0.05), blood glucose (Q1: 106.2 ± 35 vs. Q4: 109.8 ± 39 mg/dl, P < 0.005), previous cardiovascular events (Q1: 57.4 vs. Q4: 63.9%, P < 0.001), and resistant hypertension (Q1: 26.3 vs. Q4: 34.1%, P < 0.001). They also showed higher office (Q1: 143.2 ± 18 vs. Q4: 154.3 ± 19 mmHg, P < 0.001) and 24-h ambulatory SBP values (Q1: 134.8 ± 17 vs. Q4: 141.2 ± 18 mmHg, P < 0.001). Similar results were obtained when BPV was expressed as SD., Conclusion: Our study provides evidence that greater within-visit BP variabilities are associated with a worse cardiovascular risk profile. This suggests that even this type of BPV may have clinical significance.

Background and Objectives: The plasma concentration of the endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) associates with sympathetic activity in patients with CKD, but the driver of this association is unknown., Design, Setting, Participants, & Measurements: In this longitudinal study (follow-up: 2 weeks-6 months), repeated measurements over time of muscle sympathetic nerve activity corrected (MSNAC), plasma levels of ADMA and symmetric dimethylarginine (SDMA), and BP and heart rate were performed in 14 patients with drug-resistant hypertension who underwent bilateral renal denervation (enrolled in 2013 and followed-up until February 2014). Stability of ADMA, SDMA, BP, and MSNAC over time (6 months) was assessed in two historical control groups of patients maintained on stable antihypertensive treatment., Results: Time-integrated changes in MSNAC after renal denervation ranged from -40.6% to 10% (average, -15.1%), and these changes were strongly associated with the corresponding changes in plasma ADMA (r= 0.62, P=0.02) and SDMA (r=0.72, P=0.004). Changes in MSNAC went along with simultaneous changes in standardized systolic (r=0.65, P=0.01) and diastolic BP (r=0.61, P=0.02). In the historical control groups, no change in ADMA, SDMA, BP, and MSNAC levels was recorded during a 6-month follow-up., Conclusions: In patients with resistant hypertension, changes in sympathetic activity after renal denervation associate with simultaneous changes in plasma levels of the two major endogenous methylarginines, ADMA and SDMA. These observations are compatible with the hypothesis that the sympathetic nervous system exerts an important role in modulating circulating levels of ADMA and SDMA in this condition., (Copyright © 2015 by the American Society of Nephrology.)

A significant number of hypertensive subjects fail to achieve adequate blood pressure control despite adherence to maximal doses of several antihypertensive drugs. In the same way although medical and device therapies continue to improve the clinical course of heart failure patients, morbidity, mortality and healthcare costs remain high. Electrical stimulation of the carotid sinus is a new interesting approach for the treatment of resistant hypertension and heart failure. The purpose of this paper is to overview the argument starting from physiological background and evaluating the clinical results obtained with this approach in these pathophysiological conditions.

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.

It is still largely unknown whether the neuroadrenergic responses to renal denervation (RD) are involved in its blood pressure (BP)-lowering effects and represent predictors of the BP responses to RD. In 15 treated true resistant hypertensives, we measured before and 15 days, 1, 3, and 6 months after RD clinic, ambulatory and beat-to-beat BP. Measurements included muscle sympathetic nerve traffic (MSNA), spontaneous baroreflex-MSNA sensitivity, and various humoral and metabolic variables. Twelve treated hypertensives served as controls. BP, which was unaffected 15 days after RD, showed a significant decrease during the remaining follow-up period. MSNA and baroreflex did not change at 15-day and 1-month follow-up and showed, respectively, a decrease and a specular increase at 3 and 6 months after RD. No relationship, however, was detected between baseline MSNA and baroreflex, MSNA changes and BP changes. At the 6-month follow-up, the MSNA reduction was similar for magnitude in patients displaying a BP reduction greater or lower the median value. Similarly, the BP reduction detected 6 months after RD was similar in patients displaying a MSNA reduction greater or lower median value. No significant BP and MSNA changes were detected in the control group. Thus, the BP reduction associated with RD seems to precede the MSNA changes and not to display a temporal, qualitative, and quantitative relationship with the MSNA and baroreflex effects. Given the small sample size of the present study further investigations are warranted to confirm the present findings., (© 2015 American Heart Association, Inc.)

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.

Background: An increase in sympathetic drive to the heart and the peripheral circulation characterizes mild and severe essential hypertension. However, it remains unsettled whether sympathetic cardiovascular influences are potentiated in true resistant hypertension (RHT)., Methods: In 32 RHT patients treated with 4.6 ± 0.3 drugs (mean ± SEM) and aged 58.6 ± 2.1 years, 35 non-resistant treated hypertensives (HT) and 19 normotensive controls (NT), all age-matched with RHT, we measured clinic, 24-hour ambulatory and beat-to-beat blood pressures (BP), heart rate (HR, EKG), muscle sympathetic nerve traffic (MSNA, microneurography) and spontaneous baroreflex MSNA-sensitivity., Results: BP values were markedly greater in RHT patients than in NT and HT (172.2 ± 1.7/100.7 ± 1.2 vs 132.1 ± 1.3/82.1 ± 0.9 and 135.5 ± 1.2/83.6 ± 0.9 mmHg, P < 0.01). This was paralleled by a significant and marked increase in MSNA (87.8 ± 2.0 vs 46.8 ± 2.6 and 59.3 ± 1.7 and bursts/100 heartbeats, P < 0.01). In multiple regression analysis the MSNA increase observed in RHT was significantly related to hemodynamic, hormonal and metabolic variables. It was also significantly related to plasma aldosterone values as well as spontaneous baroreflex MSNA-sensitivity, which were the variables that at the multivariate analysis were more closely related to the adrenergic activation of RHT after adjustment for confounders, including antihypertensive treatment (r(2)partial=0.04405 and r(2)partial=0.00878, P<0.05 for both)., Conclusions: These data represent the first evidence that RHT is a state of marked adrenergic overdrive, greater for magnitude than that detectable in HT. They also suggest that impaired baroreflex mechanisms, along with hemodynamic and neurohumoral factors, may be responsible for the phenomenon., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The evaluation of microvascular structure is, in general, not an easy task. Among the methods that may be applied to humans, plethysmographic evaluation of small arteries and wire or pressure micromyography were extensively used in the last decades. The media-to-lumen ratio of small arteries evaluated by micromyography was demonstrated to possess a strong prognostic significance; however, its extensive evaluation is limited by the local invasiveness of the assessment. Noninvasive approaches were then proposed, including capillaroscopy, which provides information about microvascular rarefaction. Recently, the interest of investigators was focused on the retinal microvascular bed. In particular, a noninvasive measurement of the wall-to-lumen ratio of retinal arterioles using scanning laser Doppler flowmetry has been introduced.Recent data suggest a rather good agreement between this approach and micromyographic measurements, generally considered the gold standard approach. Therefore, the evaluation of microvascular structure is progressively moving from bench to bedside, and it could represent, in the immediate future, an evaluation to be performed in all hypertensive patients, in order to obtain a better stratification of cardiovascular risk.

Weight loss improves insulin sensitivity and exerts sympathomodulatory effects. No data, however, are available on the effects of the weight loss induced by vertical sleeve gastrectomy on sympathetic neural drive, insulin sensitivity, and their reciprocal cross talks. In 10 severe obese hypertensives (age, 54.0±2.3 years [mean±SEM]), we measured sphygmomanometric blood pressure, heart rate, body mass index, homeostatic model assessment index, plasma leptin, muscle sympathetic nerve traffic (microneurography), and baroreflex sensitivity (vasoactive drug technique). Measurements were performed 2 to 3 days before surgery and repeated 6 and 12 months after the procedure. Ten matched hypertensive obeses not undergoing gastrectomy served as controls. Six months after bariatric surgery, a significant (P<0.05) reduction in body mass index (-9.1±1.4 kg/m(2)), sphygmomanometric systolic blood pressure (-10.2±4.5 mm Hg), heart rate (-11.0±2.4 bpm), homeostatic model assessment index (-3-3±1.3 AU), plasma leptin (-53.6±8.8 μg/L), and muscle sympathetic nerve traffic (-15.0±3.4 bursts/100 heart beats) was observed. The weight loss, the plasma leptin reduction, and the sympathetic inhibition were maintained after 12 months, whereas homeostatic model assessment index showed a tendency to return toward presurgery values. A significant improvement in baroreflex control of sympathetic nerve traffic was observed both 6 (+32.1%; P<0.05) and 12 months (+60.7%; P<0.01) after gastrectomy. No significant changes in the above-mentioned variables were detected in the control group. These data provide evidence that massive weight loss induced by sleeve gastrectomy triggers profound sympathoinhibitory effects, associated with a stable and significant reduction in plasma leptin levels, whereas the improvement in insulin sensitivity was attenuated with time and unrelated to the sympathoinhibition., (© 2014 American Heart Association, Inc.)

A number of cardiovascular disease have been shown to be characterized by a marked increase in sympathetic drive to the heart and the peripheral circulation. This is the case for essential hypertension, congestive heart failure, cardiac arrhythmias, obesity, metabolic syndrome, obstructive sleep apnea, and chronic renal disease. This review focuses on the most recent findings documenting the role of sympathetic neural factors in the development and progression of the hypertensive state as well as in the pathogenesis of hypertension-related target organ damage. It also reviews the role of sympathetic neural factors in the development of cardiovascular diseases not necessarily strictly related to the hypertensive state, such as congestive heart failure, cardiac arrhythmias, obesity, metabolic syndrome and renal failure. The paper will finally review the pharmacological and non-pharmacological interventions acting on the sympathetic drive. Emphasis will be given to the new approaches, such as renal nerves ablation and carotid baroreceptor stimulation, which have been shown to exert sympathoinhibitory effects.

The two novel approaches recently introduced for the treatment of resistant hypertension, i.e. carotid baroreceptor stimulation and renal denervation, share a number of similarities but are also characterized by important differences. The similarities include the evidence that both interventions have as common pathophysiological background the state of sympathetic overdrive characterizing essential hypertension. In addition both procedures 1) are invasive, 2) exert in the short-term period clearcut blood pressure lowering effects and 3) still face a number of open questions, particularly related to the long-term blood pressure lowering effects, impact on end-organ damage and on cardiovascular events. The differences include the fact that two procedures act on distinct targets that trigger sympathetic activation and consequently blood pressure increase. In addition, only in the case of carotid baroreceptor stimulation the blood pressure effects can be easily assessed immediately following the implantation. Finally, the economic costs, metabolic effects and impact on vagal modulation of heart rate are different between the two interventions. This paper will provide a comparison of the background, effects and outcome of renal denervation and carotid baroreceptor stimulation, stressing whenever possible the clinical implications of the main features of the two interventions.

Objective: Scanty information is available on the clinical characteristics of resistant hypertension in Central and East European countries. The Blood Pressure (BP) control rate and CArdiovascular Risk profilE (BP-CARE) study allowed us to assess the prevalence and the main clinical features of resistant hypertension in this population., Design and Method: The study was carried out in 1312 treated hypertensive patients living in nine Central and East European countries., Results: Four hundred and twenty-three patients had apparent resistant hypertension, of whom 168 had pseudo-resistant hypertension (noncompliant/white-coat) and 255 were true treatment-resistant hypertension patients (TRH). Clinical BP values in TRH amounted to 157.4±16.9/91.8±10.0 mmHg despite the daily use of 3.6±0.7 drugs. Their 24-h BP values were 149.5±16.5/97.5±9.8 mmHg. Compared to controlled hypertensive patients (n=368) and uncontrolled nonresistant hypertensive patients (n=521), TRH were older with a greater prevalence of women. They showed a higher rate of previous cardiovascular events and a very high cardiovascular risk profile. Estimated glomerular filtration rate was significantly lower in TRH as compared to controlled hypertensive patients and uncontrolled nonresistant hypertensive patients. Overall, target organ damage was more frequently detected in TRH than in controlled hypertensive patients and uncontrolled nonresistant hypertensive patients. The factor most frequently associated with TRH was severity of hypertension followed by age, total cholesterol, BMI and history of heart failure., Conclusions: The present study provides evidence that the prevalence of TRH in Central and East European countries is similar to that found in Western Europe and USA. It also shows the very high cardiovascular risk of TRH and the elevated association of this condition with obesity, renal failure, organ damage and history of cardiovascular events.

Ambulatory blood pressure monitoring has gained growing popularity in the diagnosis and treatment of essential hypertension for several reasons, such as the lack of the so-called white-coat effect, the greater reproducibility as compared with clinic blood pressure, the ability to provide information on blood pressure phenomena of prognostic value and the closer relationship with the risk of cardiovascular morbidity and mortality. All the above-mentioned main features of ambulatory blood pressure monitoring are also true for resistant hypertension. In addition, however, in resistant hypertension, blood pressure monitoring allows one to precisely define the diagnosis of this clinical condition, by excluding the presence of white-coat hypertension, which is responsible for a consistent number of "false" resistant hypertensive cases. The approach also allows one to define the patterns of blood pressure variability in this clinical condition, as well as its relationships with target organ damage. Finally, it allows one to assess the effects of therapeutic interventions, such as renal nerves ablation, aimed at improving blood pressure control in this hypertensive state. The present paper will critically review the main features of ambulatory blood pressure monitoring in resistant hypertension, with particular emphasis on the diagnosis and treatment of this high-risk hypertensive state.

Since their introduction in the clinical setting home and ambulatory blood pressure measurements have gained growing popularity in the diagnosis and treatment of essential hypertension for a number of reasons. These reasons include: 1) the lack of the so-called "white-coat effect", 2) the ability of the two approaches to provide information on blood pressure phenomena of prognostic value, and 3) the close relationship of the derived values with the risk of developing fatal and non-fatal cardiovascular events. These features also apply to resistant hypertension, in which these approaches allow a precise definition of the diagnosis of this clinical condition, by excluding the presence of white-coat hypertension. Assessment of "out-of-office" blood pressure also allows us to define the patterns of blood pressure variability in this clinical condition as well as its relationships with target organ damage. Finally, home as well as ambulatory blood pressure measurements allow us to investigate the effects of therapeutic interventions, including those associated with the radiofrequency ablation of renal nerves. The present paper will provide a critical review of the main features of home and ambulatory blood pressure measurement in resistant hypertension, highlighting their main advantages as compared to office blood pressure. The prognostic significance, relationships with target organ damage and implications for treatment will also be discussed.

Therapeutic interventions aimed at reducing high blood pressure still encompass a number of difficulties and limitations. This is the case particularly in resistant hypertension, i.e. a condition characterized by a very high cardiovascular risk. Carotid baroreceptor stimulation and renal sympathetic nerves ablation represent new approaches in the treatment of this condition. This paper will provide a comparison of the effects of the two procedures, highlighting their effects on blood pressure, metabolic profile, target organ damage, safety and tolerability profile.

Several lines of evidence show that blood pressure (BP) control in treated hypertensive patients is largely unsatisfactory and that this depends on a variety of factors, such as the poor patient's compliance, insufficient use of combination drug treatment as well as true difficulties in achieving well controlled BP. This review article will be focused on the main features of BP control by discussing the data obtained in clinical trials as well as the results available in clinical practice. The paper will also discuss the possible factors responsible for these findings as well as the favourable outcome on cardiovascular risk profile of an effective control of elevated BP. The possible approaches for controlling elevated BP values will be highlighted.

The sympathetic nervous system is activated in a variety of cardiovascular and metabolic diseases. This is particularly the case for essential hypertension, in which various indices of adrenergic activity, such as plasma norepinephrine, norepinephrine spillover, and sympathetic nerve firing rate, are all well above the reference range of values, thereby documenting sympathetic overdrive. Evidence is available that sympathetic neural factors participate in disease progression, as well as in the development of cardiac and renal organ damage. These findings represent the rationale for therapeutic interventions that counteract the adrenergic overdrive in the hypertensive state. This paper, after reviewing the key findings of the neuroadrenergic abnormalities occurring in hypertension, examines the rationale and the technical details, as well as the results achieved so far, with the use of a new technique that allows the elimination of afferent and efferent innervation of the kidney in resistant hypertension, ie, the ablation of renal nerves. Strengths and potential limitations of the renal denervation approach are briefly addressed., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: A number of cardiovascular disease have been shown to be characterized by a marked increase in sympathetic drive to the heart and peripheral circulation. This is the case for essential hypertension, congestive heart failure, obesity, metabolic syndrome and chronic renal failure. This review focuses on the most recent findings documenting the role of sympathetic neural factors in the development and progression of the hypertensive state as well as of target organ damage. It also reviews the participation of sympathetic neural factors in the development of the earlier stages of renal failure., Recent Findings: A marked increase in sympathetic neural discharge, as assessed via the microneurographic technique, has been shown to occur in the predialytic stage of chronic renal failure. Recent evidence, however, indicates that also in the earlier clinical phases of kidney disease, sympathetic activation is detectable. Further data show that sympathetic neural mechanisms participate in renal and/or hypertensive disease progression, favouring the development of target organ damage. Finally, recent findings indicate that the metabolic disarray frequently complicating the high blood pressure state (metabolic syndrome, dislipidemia, insulin resistance) may have as pathophysiological background a sympathetic overdrive. Altogether these data represent the rationale for employing in hypertension (and particularly in resistant hypertension) therapeutic interventions such as carotid baroreceptor stimulation and renal denervation, capable of exerting sympathoinhibitory effects., Summary: The sympathetic nervous system represents a major pathophysiological hallmark of both hypertension and renal failure and is an important target for the therapeutic intervention.

Despite the proven efficacy of current strategies for cardiovascular (CV) risk reduction, a considerable gap remains between the risk reductions achieved in clinical trials and those seen in clinical practice. A major reason for this is poor compliance to medication, which has been extensively documented for antihypertensive therapy. Low adherence results in suboptimal blood pressure control, which is associated with adverse CV outcomes and increased treatment costs. Adverse effects of medication are an important cause of diminished adherence. Angiotensin II receptor blockers (ARBs) may offer better long-term tolerability than other classes of antihypertensive agent, and this is likely to be a major factor in the high levels of adherence and persistence seen with these agents. This could have implications for CV protection, as confirmed by the results of recent clinical trials. Thus, ARBs should be considered as an alternative to angiotensin-converting enzyme inhibitors in patients at risk of low adherence.

Sympathetic activation characterizes essential hypertension, contributing to the development and progression of the high blood pressure state. Throughout the years, evidence has been accumulated to show that adrenergic overdrive also participates in the pathogenesis of the end-organ damage associated with hypertension, including cardiac hypertrophy, left ventricular diastolic dysfunction, and heart failure, as well as the vascular structural and functional alterations that frequently can be detected in large, medium-size, and small arteries. Adrenergic overdrive also participates in the renal insufficiency and failure that may accompany the clinical course of the hypertensive state. This paper reviews evidence collected over the past few years documenting the importance of neurogenic factors in the development and progression of end-organ damage. The therapeutic implications of this evidence are also highlighted.

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.

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.

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.

Patients with hypertension exhibit an increased sympathetic activity. No information exists as to whether this is the case in normotensive individuals in whom there is an increased ambulatory blood pressure, a condition termed "masked" hypertension. We studied 18 middle-aged subjects with masked hypertension in whom we measured muscle sympathetic nerve traffic (peroneal nerve and microneurography) and beat-to-beat arterial blood pressure at rest and during baroreceptor deactivation and activation. Measurements also included anthropometric values and insulin sensitivity (homeostasis model assessment index). Data were compared with those of 20 normotensive subjects, 18 subjects with white-coat hypertension, and 20 patients with "in-office" and "out-of-office" hypertension. All of the individuals were pharmacologically untreated and age-matched with subjects with masked hypertension. Patients with in- and out-of-office and white-coat hypertension displayed resting sympathetic nerve activity values significantly greater than normotensive subjects (75.8+/-2.5 and 70.8+/-2.2 versus 45.5+/-2.0 bursts per 100 heartbeats respectively; P<0.01). This was the case also for masked hypertension (73.5+/-2.4 bursts per 100 heartbeats; P<0.01), the degree of the sympathetic activation being similar for magnitude to that seen in the other 2 hypertensive conditions. Compared with normotensive subjects, baroreflex-heart rate control was significantly attenuated in all of the hypertensive states, whereas baroreflex-sympathetic control was unaffected. Homeostasis model assessment index was increased in patients with in- and out-of-office and white-coat hypertension, with a further increase in masked hypertension and a direct relation with resting sympathetic nerve traffic (r=0.46; P<0.01). These data provide the first evidence that masked hypertension is characterized by a marked sympathetic overdrive. They further show that the neurogenic alterations are coupled with metabolic and baroreflex abnormalities.

Studies performed in experimental animal models of hypertension as well as in human hypertension have unequivocally shown that reflex cardiovascular control undergoes profound changes with high blood pressure and participates throughout direct and indirect mechanisms at the development and progression of hypertension-related target organ damage. This explains why investigation of the effects of antihypertensive drugs on neural cardiovascular control has a significant impact on hypertension treatment. This review will examine the main features of cardiovascular reflex control in hypertension and the effects of the different classes of antihypertensive drugs in uncomplicated and complicated hypertension.

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.