Differential effects of renal denervation on skin and muscle sympathetic nerve traffic in resistant and uncontrolled hypertension.

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.

Elevated heart rate as sympathetic biomarker in human obesity.

BACKGROUND AND AIM: The present study was aimed at determining whether and to what extent a specific heart rate (HR) cutoff value allows to identify in obeses a more pronounced level of adrenergic overdrive. METHODS AND RESULTS: In 86 obese subjects aged 44.7 ± 0.9 (mean ± SEM) years and in 45 heathy lean controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in 3 different groups according to their resting clinic and 24-h HR values (<70, 70-79 and 80-89 beats/minute). MSNA and plasma NE values detected in the three obese groups were almost superimposable each other, no significant difference between groups being observed. A similar behavior was observed when HR values were assessed during the 24-h Holter monitoring. In the group as a whole no significant relationship was detected between MSNA, plasma NE and clinic HR, this being the case also when 24-h HR replaced clinic HR in the correlation analysis. In contrast lean controls displayed a progressive significant increase in MSNA values form the group with clinic (and 24 Holter) values below 70 beats/minute to the ones with HR values between 70 and 79 and above 80 beats/minute. CONCLUSIONS: In the obese state measurement of resting HR may allow to provide some general information on the functional status of the adrenergic cardiovascular drive. When the information required, however, are more subtle the sensitivity of the approach appears to be reduced and HR cannot be regarded as a faithful sympathetic biomarker.

Autonomic Cardiovascular Alterations in Chronic Kidney Disease: Effects of Dialysis, Kidney Transplantation, and Renal Denervation.

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.

Autonomic cardiovascular alterations as therapeutic targets in 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.

Pheochromocytoma as a Clinical Model of Peripheral Sympathetic Overdrive: Old and New Findings.

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.

Sympathetic Nervous System, Sleep, and Hypertension.

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.

Sympathetic nerve traffic and blood pressure changes after bilateral renal denervation in resistant hypertension: a time-integrated analysis.

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: ß = -0.08, P = 0.08; diastolic BP versus MSNAC: ß = -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 (ß = 0.61, P < 0.001 and ß = 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.

Obesity and hypertension.

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.

Alterations in sympathetic nerve traffic in genetic haemochromatosis before and after iron depletion therapy: a microneurographic study.

AIMS: Haemochromatosis (HH) displays a number of circulatory alterations concurring at increase cardiovascular risk. Whether these include sympathetic abnormalities in unknown. METHODS AND RESULTS: In 18 males with primary HH (age: 42.3 ± 10.4 years, mean ± SD), clinic and beat-to-beat blood pressure (BP, Finapres), heart rate (HR, EKG), and muscle sympathetic nerve activity (MSNA, microneurography) traffic were measured in the iron overload state and after iron depletion therapy. Haemochromatosis patients displayed elevated serum iron indices while other haemodynamic and metabolic variables were superimposable to ones seen in 12 healthy subjects (C). Muscle sympathetic nerve activity was significantly greater in HH than C (64.8 ± 13.3 vs. 37.8 ± 6.7 bs/100 hb, P < 0.01). Iron depletion caused a significant reduction in serum ferritin, transferrin saturation, and MSNA (from 64.8 ± 13.3 to 39.2 ± 9.2 bs/100 hb, P < 0.01) and a significant improvement in baroreflex-MSNA modulation. This was paralleled by a significant increase in the high-frequency HR variability and by a significant reduction in the low-frequency systolic BP variability components. Before after iron depletion therapy, MSNA was significantly and directly related to transferrin saturation, liver iron concentration, and iron removed, while the MSNA reductions observed after the procedure were significantly and inversely related to the baroreflex-MSNA increases detected after iron depletion. In C, all variables remained unchanged following 1 month observation. CONCLUSION: These data provide the first evidence that in HH iron overload is associated with an hyperadrenergic state and a baroreflex alteration, which are reversed by iron depletion. These findings underline the importance of iron overload in modulating sympathetic activation, possibly participating at the elevated cardiovascular risk reported in HH.

Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

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.

Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications.

BACKGROUND: The sympathetic nervous exerts a key role in cardiovascular homeostasis control by regulating cardiac output, systemic vascular resistance, heart rate and blood pressure. MATERIALS AND METHODS: Data collected during the past 30 years have unequivocally shown that in a considerable number of cardiovascular as well as noncardiovascular disease there is a marked activation of the sympathetic nervous system which exerts in the long-term period unfavourable haemodynamic, metabolic, cardiovascular and renal effects. RESULTS: This paper will review the current knowledge on the alterations in sympathetic function described in cardiovascular disease, with particular focus on hypertension, heart failure and myocardial infarction. CONCLUSIONS: The consequences of the phoenomenon will be discussed together with its therapeutic implications. This will be done by examining the impact of nonpharmacological as well as pharmacological interventions on sympathetic cardiovascular drive. The effects of new invasive approaches, such as carotid baroreceptor stimulation as well as renal nerves ablation, will be also briefly discussed.

Role of ambulatory blood pressure monitoring in resistant hypertension.

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.

Differential patterns of regional neuroadrenergic cardiovascular drive in acromegalic disease.

It has been shown that acromegaly is characterized by an autonomic imbalance and by marked sympathoinhibition. However, there is no information available as to whether adrenergic inhibition is confined to selected vascular districts or, rather, is generalized. We examined 17 newly diagnosed active acromegalic patients without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy and 14 healthy subjects matched for age, sex and body mass index. For each subject, we collected information regarding anthropometric parameters and echocardiography, and collected plasma samples to investigate anterior pituitary function, glucose and lipid metabolism and plasma leptin levels. Beat-to-beat mean arterial pressure, heart rate and efferent post-ganglionic muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively; determined by microneurography) were measured. Both MSNA and SSNA were recorded in a randomized sequence over two 30 min periods. Measurements also included evaluation of SSNA responses to emotional stimulus. In addition to significant reductions in plasma leptin levels, acromegalic patients had markedly decreased MSNA compared with the healthy controls. There were no significant differences in SSNA between the two groups, either under basal conditions or in responses to arousal stimuli. There was a significant and direct correlation between MSNA and plasma leptin levels, but not between plasma leptin and SSNA. These data provide the first evidence that the sympathetic inhibition characterizing the early phase of acromegaly is not generalized to the entire cardiovascular system.

Relationships between sympathetic markers and heart rate thresholds for cardiovascular risk in chronic heart failure.

BACKGROUND: Results of recent clinical trials have shown that in heart failure (HF) heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk. No information is available on whether the sympathetic nervous system is differently activated in HF patients displaying resting HR values above or below this cutoff. METHODS: In 103 HF patients aged 62.7 ± 0.9 (mean ± SEM) years and in 62 heathy controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in different groups according to their resting clinic and 24-h HR values. RESULTS: In HF progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and NE. HR cutoff values adopted in large scale clinical trials for determining cardiovascular risk, i.e., 70 beats/minute, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for NE. In HF both MSNA and NE were significantly related to clinic (r = 0.92, P < 0.0001 and r = 0.81, P < 0.0001, respectively) and 24-h (r = 0.91, P < 0.0001 and r = 0.79, P < 0.0001, respectively) HR. The behavior of sympathetic markers described in HF was specific for this clinical condition, being not observed in healthy controls. CONCLUSIONS: Both clinic and 24-h HR values greater than 70 beats/minute are associated with an increased sympathetic activation, which parallels for magnitude the HR elevations. These findings support the relevance of using in the therapeutic approach to HF drugs exerting sympathomoderating properties.

New-onset aortic dilatation in the population: a quarter-century follow-up.

BACKGROUND: Aortic size tends to increase with aging but the extent of this dynamic process has not been evaluated in long-term longitudinal population-based studies. We investigated the incidence of new-onset aortic root (AR) dilatation and its principal correlates among middle-aged adults over a 25-year time period. METHODS: A total of 471 participants with measurable echocardiographic parameters at baseline and after a 25-year follow-up were included in the analysis. Sex-specific upper limits of normality for absolute AR diameter, AR diameter indexed to body surface area (BSA) and to height were derived from healthy normotensive PAMELA participants. RESULTS: New AR dilatation occurred in 7.4% (AR/BSA), 9.1% (AR/height) and 14.6% (absolute AR), respectively. According to the AR/height index, the risk of new dilation was similar in men and women. As for echocardiographic parameters, baseline AR diameter emerged as a key predictor of AR dilation, regardless of the diagnostic criteria and the 10-year change in LVMI was positively associated to new AR/height dilatation. No significant relationship was observed between baseline office and ambulatory systolic/diastolic blood pressure or their changes over time with incident AR dilatation. Baseline and the 25-year change in 24-h pulse pressure were negatively related to new AR dilatation. CONCLUSIONS: The incidence of AR dilatation from mid to late adulthood occurs in a small but clinically relevant fraction of participants and is unaffected by both office and out-office BP. It is significant related to baseline AR diameter and to the 25-year change in LVMI. Our data suggest that echocardiography performed in middle-aged individuals of both sexes may identify those at increased risk of future AR dilatation; moreover, preventing LVH may reduce the risk of progressive AR enlargement.

Sympathetic nervous system: role in hypertension and in chronic kidney disease.

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.

Novel antihypertensive therapies: renal sympathetic nerve ablation and carotid baroreceptor stimulation.

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.

Sympathetic nervous system and hypertension: New evidences.

Evidences collected in the past few years have strengthened the concept that the sympathetic nervous system plays a primary role in the development and progression of the hypertensive state, starting from the early stage, and in the hypertension-related cardiovascular diseases. Several pathophysiological mechanisms are involved. Among them the genetic background, the immune system in conjunction with sympathetic activation. The present review will briefly discuss the importance of the above mentioned mechanisms in the development of hypertension. The paper will also examine the sympathetic mechanisms underlying attended vs unattended blood pressure measurements as well as their role in resistant vs pseudo-resistant hypertension. Finally evidence from recent meta-analysis on the relevance of sympathetic nerve traffic activation in the pathogenesis of hypertension will be briefly discussed.

Sleep Apnea and Hypertension.

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.