Renal Norepinephrine Spillover Research Articles

Factors Influencing Muscle Sympathetic Nerve Activity in Human Heart Failure

In heart failure (HF), the magnitude of sympathetic activation predicts both disease progression and mortality. Elevated cardiac norepinephrine (NE) spillover is the earliest documented perturbation, followed later by augmented renal NE spillover and muscle sympathetic nerve activity (MSNA). To date, there is limited understanding of the mechanism(s) responsible for between‐patient variation in MSNA and cohorts studied have been small. To characterize the magnitude of MSNA discharge in HF, its inter‐patient variance, and its principal determinants, we assembled microneurographic data from 177 HF patients (28 females; 53±13 yr; LVEF: 25±11%, range 5‐60%) studied in our laboratory. Data from 658 non‐medicated, normotensive volunteers (CTRL; 260 females; 53±14 yr) acquired contemporaneously under similar conditions served as a reference group. We analyzed, at rest, fibular MSNA, blood pressure (BP), heart rate (HR), LVEF, and etiology of disease, and in a sub‐group (n=63), echocardiographically‐derived stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR). In HF, there was marked inter‐patient variance in MSNA, with burst frequency (BF) ranging from 7 to 90 bursts/minandburst incidence (BI) from 9 to 100 bursts/100 heartbeats. BF was similar in patients dispensed or not dispensed each of the three principal classes of prevailing HF therapy (all P>0.05). BF related directly (R2=0.17), and BI inversely (R2=0.09), to HR (all P<0.001); neither correlated with BP. For each kg/m2 rise in BMI, BF increased, on average, by 0.20 bursts/min (95% CI, 0.02‐0.37; P=0.03); its relation to BI was less pronounced (P=0.05). BF increased non‐linearly when LVEF fell below ~21% (P<0.01); above this inflection point, BF displayed no relationship with LVEF. Overall, LVEF accounted for only 9.8% of the variance in BF (P=0.001), while no relationship existed between LVEF and BI (R2=0.007). BI (P=0.01), but not BF (P=0.14), was greater in patients with ischemic vs. dilated cardiomyopathy. BF and BI exhibited non‐linear, inverse relationships with SV (R2=0.31 and 0.12; all P<0.01) and CO (R2=0.17 and 0.20; all P<0.01), and a non‐linear, direct relationship with TPR (R2=0.18 and 0.21; all P<0.01). Unadjusted BF (52±15 vs. 26±13 bursts/min; P<0.001) was elevated in HF vs. CTRL. With age, BF exhibited little or no change in HF, in contrast to its non‐linear increase in CTRL. BF, adjusted for age, sex, BMI, and HR, was significantly greater throughout the lifespan (estimate 14.20 bursts/min; 95% CI, 12.11‐16.28; P<0.001) in HF, relative to CTRL, and higher in men than in women (estimate 5.01 bursts/min; 95% CI, 3.42‐6.61; P<0.001). Overall, the extent of sympathetic excess in HF, relative to CTRL, diminished with age. In conclusion, resting MSNA in HF is a function of etiology, BMI, HR, LVEF and SV, but not age; these relationships are significant but moderate to weak, as is that between sympathetic vasoconstrictor discharge and TPR. These observations provide insight into the complexity and individual specificity of mechanisms eliciting muscle sympathetic excitation in human HF.

Evaluation of elevated heart rate as a sympathetic nervous system biomarker in essential hypertension.

There is a need for an easily accessible biomarker of sympathetic nervous activation in essential hypertension, but none exists. Heart rate (HR) has been suggested, but requires validation, now doubly important as an elevated HR in hypertension has emerged as an independent cardiovascular risk factor. Isotope dilution methodology was used to measure total and regional noradrenaline spillover and adrenaline secretion rates in 30 patients with unmedicated essential hypertension and in a comparator group of 48 healthy participants with normal blood pressure. The particular interest was in the relationship of measured HR to cardiac noradrenaline spillover, the measure of cardiac sympathetic activity. Sympathetic activation was present in the patients with essential hypertension, evident in significantly increased mean cardiac, renal and total noradrenaline spillover rates. Adrenaline secretion was normal. HR in hypertension correlated directly with cardiac noradrenaline spillover (r = 0.82, P = 9.3 × 10), but not with renal noradrenaline spillover or adrenaline secretion. 67% of the variance in HR was attributable to differences in cardiac sympathetic activity. Among hypertensive patients there was no internal correlation between cardiac noradrenaline spillover, renal noradrenaline spillover and adrenaline secretion; the sympathetic activation commonly was not 'global'. In healthy participants HR did not correlate with measures of sympathetic activity or adrenaline secretion. When sympathetic activation exists in essential hypertension it is differentiated, not necessarily involving all sympathetic outflows. An elevated HR proved to be a biomarker of cardiac sympathetic activation but not activation of the renal sympathetic outflow. Identifying activation of the cardiac sympathetic outflow as the prime mechanism of hypertension tachycardia is relevant to therapies which should now be considered to minimize cardiovascular risk in this clinical setting. Is an elevated HR a valid biomarker of sympathetic activation in essential hypertension? Yes, but only for the cardiac sympathetic outflow. The unavoidable principle is that regional differentiation of sympathetic responses in essential hypertension means that no simple test can ever represent each and every sympathetic outflow.

Neurohumoral interactions contributing to renal vasoconstriction and decreased renal blood flow in heart failure

In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α1-adrenoceptors. In conscious sheep with mild HF (ejection fraction 35%-40%), renal blood flow (276 ± 13 to 185 ± 18 mL/min) and renal vascular conductance (3.8 ± 0.2 to 3.1 ± 0.2 mL·min-1·mmHg-1) were decreased compared with healthy sheep. There were increases in the burst frequency of RSNA (27%), renal norepinephrine spillover (377%), and plasma renin activity (141%), whereas the density of renal medullary angiotensin type-1 receptors decreased. In anesthetized sheep with HF, the renal vasoconstrictor responses to electrical stimulation of the renal nerves or to phenylephrine were attenuated. Irbesartan improved the responses to nerve stimulation, but not to phenylephrine, in HF and reduced the responses in normal sheep. In summary, in HF, the increases in renal norepinephrine spillover and plasma renin activity are augmented compared with the increase in RSNA. The vasoconstrictor effect of the increased renal norepinephrine and angiotensin II is offset by reduced levels of renal angiotensin type-1 receptors and reduced renal vasoconstrictor responsiveness to α1-adrenoceptor stimulation.

Renal Sympathetic Hyperactivity in Hypertension: True or False?

Increased renal norepinephrine spillover, observed by using isotope-dilution method, is thought to indicate renal sympathetic hyperactivity and to play a crucial role in hypertension. However, SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension), the first randomized sham-controlled trial, failed to show a benefit of renal denervation for resistant hypertension.1 This raises the issue of whether the sympathetic hyperactivity hypothesis is true. In a recent issue of Circulation Research , Grassi et al2 have emphasized the presence and importance of sympathetic hyperactivity in hypertension, primarily based on the results of isotope-dilution studies. However, the isotope-dilution method cannot exclude the involvement of intraorgan platelet release of norepinephrine. We would argue that platelet norepinephrine release, rather than sympathetic nervous system alterations, may be the cause of increased norepinephrine spillover in hypertension for …

“Won’t Get Fooled Again”

Early trials demonstrated that renal artery denervation (RDN), delivered with a catheter in the renal artery, reduced blood pressure by reducing sympathetic tone in patients with hypertension, as measured by renal norepinephrine spillover and muscular sympathetic nerve activity [(1)][1]. SYMPLICITY

Abstract 17410: Catheter-based Radiofrequency Renal Denervation Decreases Renal Norepinephrine Spillover and Improves Cardiac Contractile Function in a Porcine Model of Ischemic Heart Failure

Background: Catheter-based radiofrequency (RF) renal denervation (RD) has been shown to decrease renal norepinephrine (NE) spillover in animal models and humans with hypertension. Nevertheless, the effect of RD on renal NE spillover in systolic heart failure (HF) is unknown. Methods: Ischemic HF model was created in 16 porcine by inducing myocardial infarction (MI) via coronary embolization of the left circumflex artery followed by rapid ventricular pacing for 4 weeks (MI+HF). Of these, 8 porcine underwent bilateral RD using the EnligHTN System (St. Jude Medical) and the remaining 8 served as control. All animals were given daily oral metoprolol ZOK (50 mg) plus ramipril (2.5 mg). Serum NE levels at different sites and index of cardiac contractility (dP/dt max /IP) were measured at baseline, immediately after MI (post-MI), at MI+HF and at 10 weeks follow-up. Renal arteries were then prepared for histological analysis. Results: RD significantly increased the dP/dt max /IP as compared with the control group (P<0.05, Figure 1a). RD also decreased the arterial and coronary sinus NE (P<0.05), and renal NE spillover (-54%, P=0.06) at 10 weeks as compared with MI+HF (Figures 1b & 1c). Histological examination showed significant reduction of renal sympathetic efferent nerves (tyrosine hydroxylase+) at proximal, middle and distal portions of the renal artery after RD as compared with the control group (-65%, P<0.05, Figure 1d). Conclusions: In a porcine model of ischemic HF, bilateral RD using catheter-based RF effectively destroys renal nerves to decrease renal NE spillover, and improves LV contractile function compared with medical therapy alone.

Abstract 10452: The SYMPLICITY HF Feasibility Study: Twelve Month Outcomes of Renal Denervation in Patients With Chronic Heart Failure and Renal Impairment

Introduction: Renal dysfunction often develops in patients with heart failure with low ejection fraction due to hemodynamic and neurohumoral dysfunction leading to increased risk for mortality. Methods: The multi-center, prospective, open label Renal Denervation in Patients With Chronic Heart Failure & Renal Impairment (SYMPLICITY HF) trial enrolled NYHA Class II-III patients with left ventricular ejection fraction (LVEF) <40% and estimated glomerular filtration rate (eGFR) 30 to 75 mL/min/1.73m 2 . Subjects with systolic blood pressure < 90 mm Hg were excluded. The primary objective was to evaluate both the safety and physiologic response of renal denervation therapy on cardiac and renal function with the Symplicity™ renal denervation system using the Symplicity Flex™ catheter (Medtronic, Inc). Results: A total of 39 patients were enrolled (Table). No vascular complications occurred during the procedure. Available at AHA 2015 will be outcomes to 12 months follow up, including safety, cardiac function by echocardiography, and renal function by eGFR. Additionally, 9 subjects participated in a sub study that evaluated cardiac and renal noradrenaline spillover, muscle sympathetic nerve activity, and electrophysiological parameters by Holter monitor. Conclusions: Twelve-month outcomes in SYMPLICITY HF will provide initial insights into the safety and cardiac and renal physiologic impact of renal denervation in patients with heart failure.

The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications

Renal sympathetic activation plays a key role in the pathogenesis of hypertension, as demonstrated by high renal norepinephrine spillover into plasma of patients with essential hypertension. Renal denervation has demonstrated a significant reduction in blood pressure in unblinded studies of hypertensive patients. The SYMPLICITY HTN-3 trial, the first prospective, masked, randomized study of renal denervation versus sham control, failed its primary efficacy end point and raised important questions around potentially confounding factors, such as drug changes and adherence, study population, and procedural methods. The SPYRAL HTN Global Clinical Trial Program is designed to address limitations associated with predicate studies and provide insight into the impact of pharmacotherapy on renal denervation efficacy. The 2 initial trials of the program focus on the effect of renal denervation using the Symplicity Spyral multielectrode renal denervation catheter in hypertensive patients in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. The SPYRAL HTN ON-MED study requires patients to be treated with a consistent triple therapy antihypertensive regimen, whereas the SPYRAL HTN OFF-MED study includes a 3- to 4-week drug washout period followed by a 3-month efficacy and safety end point in the absence of antihypertensive medications. The studies will randomize patients with combined systolic-diastolic hypertension to renal denervation or sham procedure. Both studies allow renal denervation treatments in renal artery branches and accessories. These studies will inform the design of the second pivotal phase of the program, which will more definitively analyze the antihypertensive effect of renal denervation.

Regulation of the renal sympathetic nerves in heart failure.

Heart failure (HF) is a serious debilitating condition with poor survival rates and an increasing level of prevalence. HF is associated with an increase in renal norepinephrine (NE) spillover, which is an independent predictor of mortality in HF patients. The excessive sympatho-excitation that is a hallmark of HF has long-term effects that contribute to disease progression. An increase in directly recorded renal sympathetic nerve activity (RSNA) has also been recorded in animal models of HF. This review will focus on the mechanisms controlling sympathetic nerve activity (SNA) to the kidney during normal conditions and alterations in these mechanisms during HF. In particular the roles of afferent reflexes and central mechanisms will be discussed.

Changes in Directly Recorded Sympathetic Nerve Activity and Noradrenaline Spillover to the Heart and Kidney during Heart Failure

Heart failure (HF) is associated with increased cardiac and renal noradrenaline (NA) spillover, both of which are independent predictors of mortality. We hypothesized that in HF changes in the mechanisms controlling NA release and uptake would lead to differences between directly recorded sympathetic nerve activity (SNA) and NA spillover to the heart and kidney. Experiments were conducted in conscious sheep implanted with cardiac SNA (CSNA) and renal SNA (RSNA) recording electrodes. Together with recordings of SNA and arterial pressure, the spillover of NA from both the heart and the kidney was determined. HF was associated with a two‐fold increase in CSNA (42±8 vs. 95±11 bursts/100hb, p<0.05) but a five‐fold increase in cardiac NA spillover (3.1±0.8 vs. 18.1±4.1 pmol/min, p<0.05). Infusion of sodium nitroprusside in the normal animals significantly increased CSNA to levels similar to those in HF, but the level of cardiac NA spillover (7.1±1.6) reached only 50% of that in HF. Further increases in CSNA in the HF animals were not associated with any further increases in cardiac NA spillover. In HF, RSNA was unchanged (95±8 bursts/100hb), but interestingly spillover of NA from the kidney was significantly increased (10.1±2.4 vs. 52.5±10.2 pmol/min, p<0.05). The mismatch between CSNA and cardiac NA spillover in HF suggests that other mechanisms such as the NA transporter may play an important role in mediating the increased cardiac NA spillover. Further experiments are required to determine what causes the discordance between the baseline levels of RSNA and renal NA spillover in HF.

Reinnervation of afferent and efferent nerves after catheter‐based renal denervation in sheep

Previous studies indicate that catheter-based renal denervation (RDN) reduces blood pressure and renal noradrenaline spillover in resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We examined the level of reinnervation 5.5 and 11 months after RDN using the Symplicity Flex catheter. Catheter-based RDN effectively ablated afferent and efferent nerves within the kidney. Eleven months after RDN, reinnervation was shown by the return of renal sympathetic nerve activity, normal responses to electrical stimulation and normal distribution of afferent and efferent nerves within the kidney. In addition we investigated the effects of catheter denervation on the nerves surrounding the renal arteries and changes within the dorsal root ganglia. In view of these data, the mechanisms underlying the prolonged hypotensive effect of catheter-based RDN in human resistant hypertension need to be reassessed. This work was supported by the National Health and Medical Research Council of Australia and the Victorian Government's Operational Infrastructure Support Program.

Renal denervation in resistant arterial hypertension: Effects on neurohormonal activation and cardiac natriuretic peptides

Renal denervation (RD) is an emerging treatment for resistant arterial hypertension (RAH). RAH is characterized by hyperactivity of catecholaminergic and renin–angiotensin–aldosterone systems (RAAS), with elevated arterial blood pressure and a higher prevalence of cardiovascular overload and remodeling. As renal innervation is involved in sympathetic and RAAS overactivation, RD has the potential to reduce blood pressure by influencing this pathophysiological network [1]. Indeed, RD has been shown to reduce renal norepinephrine spillover [2] and it seems to exert beneficial effects also on cardiac remodeling by reduction of cardiac hypertrophy [3].

Renal sympathetic nerves – what have they got to do with cardiovascular disease?

What is the topic of this review? This review examines the role played by renal sympathetic nerves in the regulation of cardiovascular function, focusing on changes that occur during the development of hypertension and heart failure. What advances does it highlight? While elevated levels of renal sympathetic activity are a feature of many cardiovascular diseases, the relationship is not straightforward, especially in the case of hypertension. This review highlights that before consideration of targeting the renal nerves in the clinical management of cardiovascular diseases it is essential that their role in the development of the disease is established. In recent years, with the development of new clinical techniques to target the renal nerves specifically, we have seen a renewed interest in the role of the renal sympathetic nerves in the development of cardiovascular diseases. In understanding the potential of renal nerve ablation for the treatment of cardiovascular disease, first the role played by these nerves in cardiovascular regulation must be determined. Elevated renal sympathetic activity not only has the potential to increase fluid retention but may also act in a feedforward manner to increase sympathetic activation further, increasing the workload of the heart and the potential for arrhythmias. Direct recordings of renal sympathetic nerve activity in animal models of hypertension and renal noradrenaline spillover levels in individual patients with hypertension have illustrated that hypertension is not always accompanied by an increase in renal sympathetic activity. Elevated renal sympathetic nerve activity is a feature of severe heart failure, but whether removal of the renal nerves then compromises the ability to maintain cardiac function when faced with a stressor such as sepsis remains unclear. Understanding when increased renal sympathetic drive is contributing to the progression of cardiovascular diseases such as hypertension and heart failure would appear to be the key to understanding when renal nerve ablation is likely to be of benefit.

Reinnervation of renal afferent and efferent nerves at 5.5 and 11 months after catheter-based radiofrequency renal denervation in sheep.

Previous studies indicate that catheter-based renal denervation reduces blood pressure and renal norepinephrine spillover in human resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We therefore examined the level of functional and anatomic reinnervation at 5.5 and 11 months after renal denervation using the Symplicity Flex catheter. In normotensive anesthetized sheep (n=6), electric stimulation of intact renal nerves increased arterial pressure from 99±3 to 107±3 mm Hg (afferent response) and reduced renal blood flow from 198±16 to 85±20 mL/min (efferent response). In a further group (n=6), immediately after denervation, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. At 11 months after denervation (n=5), renal sympathetic nerve activity and the responses to electric stimulation were at normal levels. Immunohistochemical staining for renal efferent (tyrosine hydroxylase) and renal afferent nerves (calcitonin gene-related peptide), as well as renal norepinephrine levels, was normal 11 months after denervation. Findings at 5.5 months after denervation were similar (n=5). In summary, catheter-based renal denervation effectively ablated the renal afferent and efferent nerves in normotensive sheep. By 11 months after denervation the functional afferent and efferent responses to electric stimulation were normal. Reinnervation at 11 months after denervation was supported by normal anatomic distribution of afferent and efferent renal nerves. In view of this evidence, the mechanisms underlying the prolonged hypotensive effect of catheter-based renal denervation in human resistant hypertension need to be reassessed.

Sympathetic Nervous System Moves Toward Center Stage in Cardiovascular Medicine

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …

The Effect of Renal Sympathetic Denervation (RSD) in Atrial Fibrillation (AF) Inducibility

Objective: The purpose of this study is to investigate the effects of renal sympathetic nerve stimulation (RSN-S) and ablation (RSN-A) on atrial effective refractory period (ERP) and AF in normal canine heart. Atrial Fibrillation (AF) is a complex disease and one of the most frequent arrhythmias, especially in elderly patients. Multiple mechanisms are involved including interaction between the autonomic nervous system (ANS), electrophysiological properties of the atria, and vulnerability for AF. Cardiac overload increases the incidence of AF. In lone AF the triggers are in the pulmonary veins. AF caused by underlying disease has different mechanism. Atrial fibrillation (AF) is associated with activity of renin-angiotensin-aldosterone system (RAAS). Reduction in renal nor-adrenaline spillover could be achieved after renal sympathetic denervation (RSD). Methods: 1) Establish of atrial fibrillation model; 2) Ventricular rate analysis of AF; 3) Statistical analysis. Results: 1) The establishment of atrial fibrillation model; 2) Inducibility and duration of AF; 3) The changes of AERP dispersion. Conclusion: Left RSN-S shortened left atrial ERP, increased ERP dispersion, but did not change right atrial ERP. Bilateral RSN-A produced significant prolongation in both atrial ERP, but did not affect ERP dispersion. The on time of RD effect is at 4 hrs after RD procedure and the RD effect on AF will last for 20 hrs after RD procedure.

Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease

Sympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known. In an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond. Average office BP was 170.8 ± 16.9/89.2 ± 12.1 mmHg despite the use of 3.8 ± 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 ± 16.0 to 148 ± 11, 150 ± 14, and 138 ± 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment. RDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD.

Clinical Implications

HomeHypertensionVol. 61, No. 2Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Feb 2013https://doi.org/10.1161/HYP.0b013e318284b8b8Hypertension. 2013;61:267Autoantibodies in Primary Aldosteronism (page 526)Primary aldosteronism (PA) is the most frequent endocrine cause of hypertension. The differential diagnosis between its 2 main subtypes, for example—aldosterone-producing adenoma and idiopathic hyperaldosteronism, is the key for selecting surgical or medical treatment, but challenging.In this study, we detected autoantibodies against the AT1 receptor (AT1AA) at a raised titer in serum of PA patients, and particularly in those with an aldosterone-producing adenoma as compared with those with idiopathic hyperaldosteronism or essential hypertension with similar blood pressure (BP) elevation. Of clinical relevance, the AT1AA titer provided a discrimination of aldosterone-producing adenoma from idiopathic hyperaldosteronism, thus suggesting that the AT1AA titer can help in selecting the PA patients to be submitted to adrenal vein sampling. The latter test, which is expensive, invasive, and not widely available, is recommended by the Endocrine Society Guidelines in all patients who are candidates for adrenalectomy.Finally, the mechanisms underlying PA have eluded identification thus far notwithstanding a long quest. As these AT1AA are suggested to play an agonistic effect, including stimulation of aldosterone secretion, their presence in aldosterone-producing adenoma patients could explain the persistent over-secretion of aldosterone in spite of the high BP, the suppression of the renin-angiotensin system and the hypokalemia, all factors that would be expected to blunt aldosterone secretion. Hence our data might shed a new light on the pathophysiology of PA.Download figureDownload PowerPointRenal Denervation and Sympathetic Activity (page title>Autoantibodies in Primary Aldosteronism (page 457)Catheter-based renal denervation has emerged as a novel treatment option for patients with resistant hypertension. The limited number of studies available thus far suggest that the procedure is safe and results in a significant and sustained BP reduction in the majority of treated patients with resistant hypertension. Although ablation of efferent renal nerves, as evident form a mean reduction in renal noradrenaline spillover of 47%, is likely to contribute to the BP lowering effects via alteration of renin release, renal blood flow, and tubular sodium retention, inhibition of central sympathetic outflow has also been documented by applying multiunit muscle sympathetic nerve activity recordings.Here, we examined whether renal denervation may differentially influence the sympathetic discharge pattern of single vasoconstrictor neurons in patients with resistant hypertension and found that all properties of single-unit muscle sympathetic nerve activity, including firing rates of individual vasoconstrictor fibers, firing probability, and multiple firing incidence of single units within a cardiac cycle, were substantially reduced. These findings indicate that renal denervation may restrain abnormal patterns of sympathetic nerve firing commonly evident in patients with resistant hypertension and exhibit renal signaling via afferent nerves projecting to certain brain stem nuclei as a likely contributor to the BP rise in resistant hypertension.Download figureDownload PowerPointCombination Therapy, CV Events, and BP Control (page Sympathetic Activity (page title>Autoantibodies in Primary Aldosteronism (page 309)Combination therapy is required to achieve current BP targets in ≈75% of hypertensive patients. Previous studies indicate that initial use of a combination accelerates the time course over which BP control is attained. However, the optimal time frame for achieving BP control in clinical practice has never been defined, and criteria for using initial combination therapy remain uncertain. In a retrospective, matched cohort study, the impact of initial versus delayed combination therapy on the risk of developing a cardiovascular (CV) event was assessed in a community practice setting. The mean baseline BP was ≈150/85 mm Hg, and two thirds had stage I hypertension. Initial combination treatment led to more rapid and more effective BP control and was associated with a 34% risk reduction for CV events or death relative to patients initiated on monotherapy and subsequently uptitrated to combination treatment by their practicing physicians. Fewer patients who experienced a CV event achieved target BP, and on-treatment BP parameters accounted for most of the difference in CV event rates.Initial combination therapy was also associated with a significant reduction in healthcare resource utilization. These results suggest that combination therapy should be initiated routinely in most patients likely to require multiple agents to reach goal BP, and that initial combination therapy is a superior treatment strategy for a large segment of the hypertensive population including many patients with mild hypertension.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails February 2013Vol 61, Issue 2 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/HYP.0b013e318284b8b8 Originally publishedFebruary 1, 2013 PDF download Advertisement

The hypothalamic paraventricular nucleus may not be at the heart of sympathetic outflow

Heart failure (HF) is associated with activation of various neurohumoral factors including the renin–angiotensin–aldosterone and sympathetic nervous systems. In HF patients, elevated sympathetic nerve activity (SNA) is reflected by increased whole body, as well as regional (e.g. cardiac and renal) noradrenaline spillover (Kaye et al. 1994; Petersson et al. 2005), and increased sympathetic nerve discharge (Leimbach et al. 1986). Importantly, the degree of sympathoexcitation predicts mortality in HF patients (Petersson et al. 2005). Consequently, an immense amount of research effort has been directed towards the identification of mechanisms and circuitry underlying elevated SNA in HF. Neurons of the hypothalamic paraventricular nucleus (PVH) regulate SNA in a variety of physiological conditions and pathophysiological states through mono- and polysynaptic projections to the medulla and spinal cord (Guyenet, 2006). Evidence from studies, largely conducted in anaesthetized rodents, suggests HF activates PVH neurons through a reduction in GABAergic function (Patel, 2000). A critical question is the extent to which PVH neurons contribute to elevated SNA in HF. In this issue of The Journal of Physiology, Ramchandra and colleagues (2013) provide novel data utilizing chronic SNA recordings in conscious sheep to address this important question. Interruption of PVH neurotransmission by radiofrequency ablation or neuronal inhibition by microinjection of glycine or the GABAA agonist muscimol failed to lower cardiac and/or renal SNA in both control and HF sheep. Furthermore, blockade of PVH GABAA receptors with injection of bicuculline increased cardiac SNA, mean arterial blood pressure and heart rate in control but not HF sheep. The absence of sympathetic-cardiovascular responses to GABAA receptor activation or blockade in HF versus control sheep confirms a reduced GABAergic function in the PVH. More importantly, these findings challenge the general notion that PVH neurons contribute to sympathoexcitation in HF. Several issues may explain the discrepancies between the present and past studies: (1) differences between anaesthetized versus conscious animals, (2) differences in the central nervous system circuitry/mechanisms between HF models (i.e. coronary ligation versus ventricular pacing), and (3) the possibility that PVH neurons contribute to the development, but not maintenance, of elevated SNA in HF. A second intriguing finding is the differential contribution of PVH neurons to cardiac and renal sympathoinhibitory responses to volume expansion. In conscious sheep, PVH inhibition with injection of the GABAA agonist muscimol reversed the renal, but not the cardiac, sympathoinhibition during intravenous infusion of gelofusine. At least two critical questions arise from these findings. First, PVH neurons abundantly express the vesicular glutamate transporter but are not GABAergic (e.g. GAD67 positive) (Stocker et al. 2006). If volume expansion reduces the discharge of spinally projecting PVH neurons (Lovick & Coote, 1988), why does further inhibition using muscimol reverse the sympathoinhibition? Second, how do PVH neurons differentially regulate SNA to various end organs? The notion that PVH neurons can selectively increase SNA to one organ but not to another has been reported previously (Deering & Coote, 2000; Ward et al. 2011). Therefore, are there distinct populations of PVH neurons that regulate renal versus cardiac versus muscle SNA? Do these neurons receive different anatomical and neurochemical inputs? Previous studies have utilized transneuronal viruses to map the neuronal circuitry associated with a specific end-organ, but limited data exist to demonstrate whether PVH and other central nuclei contain overlapping or distinct populations of neurons to permit differential regulation of SNA. The findings of Ramchandra and colleagues (2013) provide evidence against a role of PVH neurons in elevating SNA in HF but emphasize the ability of PVH neurons to differentially control sympathetic outflow to distinct end-organs. The present findings highlight our limited understanding of how many CNS structures are anatomically and neurochemically connected to coordinate sympathetic outflow to a variety of organs.

Application in Hypertension of Renal Sympathetic Denervation - A Review.

Afferent and efferent sympathetic nerves of the kidney located in the adventitia of the renal artery are involved in the regulation of blood pressure and play a pathophysiological role in the progression and maintenance of hypertension. Renal sympathetic denervation is a potent and safe catheter-based therapeutic approach for the treatment of patients with resistant hypertension. Clinical trials of renal sympathetic denervation have shown significant reduction in blood pressure, which was associated with a reduction in local renal norepinephrine spillover as well as a reduction of whole body sympathetic activation in resistant hypertensive patients.