Renal Denervation in End-Stage Renal Disease: Current Evidence and Perspectives.

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

Possible organ-protective effects of renal denervation: insights from basic studies.

Inappropriate sympathetic nervous activation is the body's response to biological stress and is thought to be involved in the development of various lifestyle-related diseases through an elevation in blood pressure. Experimental studies have shown that surgical renal denervation decreases blood pressure in hypertensive animals. Recently, minimally invasive catheter-based renal denervation has been clinically developed, which results in a reduction in blood pressure in patients with resistant hypertension. Accumulating evidence in basic studies has shown that renal denervation exerts beneficial effects on cardiovascular disease and chronic kidney disease. Interestingly, recent studies have also indicated that renal denervation improves glucose tolerance and inflammatory changes. In this review article, we summarize the evidence from animal studies to provide comprehensive insight into the organ-protective effects of renal denervation beyond changes in blood pressure.

Acute Modulation of Left Ventricular Control by Selective Intracardiac Sympathetic Denervation.

BACKGROUND: The sympathetic nervous system plays an integral role in cardiac physiology. Nerve fibers innervating the left ventricle are amenable to transvenous catheter stimulation along the coronary sinus (CS). OBJECTIVES: The aim of the present study was to modulate left ventricular control by selective intracardiac sympathetic denervation. METHODS: First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of decentralized murine hearts (n = 10 each, ablation and control groups). Second, the impact of transvenous, anatomically driven axotomy by catheter-based radiofrequency ablation via the CS was evaluated in healthy sheep (n = 8) before and during stellate ganglion stimulation. RESULTS: CS ablation prolonged epicardial ventricular refractory period without (41.8 ± 8.4 ms vs 53.0 ± 13.5 ms; P = 0.049) and with ß1-2-adrenergic receptor blockade (47.8 ± 7.8 ms vs 73.1 ± 13.2 ms; P < 0.001) in mice. Supported by neuromorphological studies illustrating a circumferential CS neural network, intracardiac axotomy by catheter ablation via the CS in healthy sheep diminished the blood pressure increase during stellate ganglion stimulation (Δ systolic blood pressure 21.9 ± 10.9 mm Hg vs 10.5 ± 12.0 mm Hg; P = 0.023; Δ diastolic blood pressure 9.0 ± 5.5 mm Hg vs 3.0 ± 3.5 mm Hg; P = 0.039). CONCLUSIONS: Transvenous, anatomically driven axotomy targeting nerve fibers along the CS enables acute modulation of left ventricular control by selective intracardiac sympathetic denervation.

Effects of Renal Denervation on Sympathetic Nerve Traffic and Correlates in Drug-Resistant and Uncontrolled Hypertension: A Systematic Review and Meta-Analysis.

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

Post-ablation augmentation of skin sympathetic nerve activity predicts a poor outcome of idiopathic ventricular arrhythmias.

BACKGROUND: The neuromodulation effect after ventricular arrhythmia (VA) ablation is unclear. The study aimed to investigate skin sympathetic nerve activity (SKNA) changes in patients receiving catheter ablations for idiopathic VA. METHODS: Of 43 patients with drug-refractory symptomatic VA receiving ablation, SKNA was continuously recorded for 10 min during resting from electrocardiogram lead I configuration and bipolar electrodes on the right arm 1 day before and 1 day after ablation. RESULTS: Twenty-two patients with acute procedure success and no recurrence during follow-ups were classified as sustained success group (group 1). Other 21 patients were classified as failed ablation group (group 2). Baseline SKNA showed no significant difference between the two groups. Post-ablation SKNA in group 2 was significantly higher than in group 1. In patients with ablation involved right ventricular outflow tract (RVOT), the post-ablation SKNA was also significantly higher in group 2. In contrast, there was no difference in post-ablation SKNA between groups in patients receiving non-RVOT ablation. CONCLUSION: The neuromodulation response after RVOT ablation may correspond to the sympathetic nerve distribution at RVOT. Augmentation of sympathetic activity after VA ablation indicates an unsuccessful VA suppression, especially in patients receiving ablation of RVOT VA.

Rationale and Design of Sympathetic Mapping/Ablation of Renal Nerves Trial (SMART) for the Treatment of Hypertension: a Prospective, Multicenter, Single-Blind, Randomized and Sham Procedure-Controlled Study.

Renal denervation (RDN) is proposed as a durable and patient compliance independent treatment for hypertension. However, 20-30% non-responder after RDN treatment weakened the therapeutic effect, which may be due to blind ablation. The renal nerve mapping/selective ablation system developed by SyMap Medical Ltd (Suzhou), China, has the function of mapping renal sympathetic/parasympathetic nerve sites and selectively removing renal sympathetic nerves and is expected to meet the urgent unmet clinical need of targeted RDN. The "Sympathetic Mapping/Ablation of Renal Nerves Trial" (SMART) is a prospective, multicenter, randomized, single-blinded, sham procedure-controlled trial, to evaluate the safety and efficacy of targeted renal sympathetic denervation in patients with essential and uncontrolled hypertension. The study is the first clinical registry trial using a targeted RDN for the treatment of uncontrolled hypertension; the dual-endpoint design can answer the question of how many antihypertensive drugs can be reduced in patients after RDN. The trial is registered on clinicaltrials.gov NCT02761811.

Surgical Technique for Superior Cervical Ganglionectomy in a Murine Model.

Growing evidence suggests that the sympathetic nervous system plays an important role in cancer progression. Adrenergic innervation regulates salivary gland secretion, circadian rhythm, macular degeneration, immune function, and cardiac physiology. Murine surgical sympathectomy is a method for studying the effects of adrenergic innervation by allowing for complete, unilateral adrenergic ablation while avoiding the need for repeated pharmacologic intervention and the associated side effects. However, surgical sympathectomy in mice is technically challenging because of the small size of the superior cervical ganglion. This study describes a surgical technique for reliably identifying and resecting the superior cervical ganglion to ablate the sympathetic nervous system. The successful identification and removal of the ganglion are validated by imaging the fluorescent sympathetic ganglia using a transgenic mouse, identifying post-resection Horner's syndrome, staining for adrenergic markers in the resected ganglia, and observing diminished adrenergic immunofluorescence in the target organs following sympathectomy. This model enables future studies of cancer progression as well as other physiological processes regulated by the sympathetic nervous system.

Effects and mechanism of renal denervation on ventricular arrhythmia after acute myocardial infarction in rats.

BACKGROUND: Renal denervation (RDN) can reduce ventricular arrhythmia after acute myocardial infarction (AMI), but the mechanism is not clear. The purpose of this study is to study its mechanism. METHODS: Thirty-two Sprague-Dawley rats were divided into four groups: control group, AMI group, RDN-1d + AMI group, RDN-2w + AMI group. The AMI model was established 1 day after RDN in the RDN-1d + AMI group and 2 weeks after RDN in the RDN-2w + AMI group. At the same time, 8 normal rats were subjected to AMI modelling (the AMI group). The control group consisted of 8 rats without RDN intervention or AMI modelling. RESULTS: The study confirmed that RDN can reduce the occurrence of ventricular tachycardia in AMI rats, reduce renal sympathetic nerve discharge, and inhibit the activity of local sympathetic nerves and cell growth factor (NGF) protein expression in the heart after AMI. In addition, RDN decreased the expression of norepinephrine (NE) and glutamate in the hypothalamus,and NE in cerebrospinal fluid, and increased the expression level of γ aminobutyric acid (GABA) in the hypothalamus after AMI. CONCLUSION: RDN can effectively reduce the occurrence of ventricular arrhythmia after AMI, and its main mechanism may be via the inhibition of central sympathetic nerve discharge.

Anatomical variations of the upper thoracic sympathetic chain: a review.

ABSTRACT OBJECTIVES: The objective of this study is to provide a thorough overview of the anatomical variations of the upper thoracic sympathetic trunk to improve clinical results of upper thoracic sympathectomy. In addition, this study strives for standardization of future studies regarding the anatomy of the upper thoracic sympathetic chain. METHODS: The Web of Science, PubMed and Google Scholar databases were searched using keywords, alone or combined, regarding the anatomy of the thoracic sympathetic chain. The search was limited to studies performed in humans. RESULTS: Fifteen studies were finally included. Cervicothoracic ganglion and nerve of Kuntz were present in 77% and 53%, respectively. The upper thoracic ganglia were predominantly located in their corresponding intercostal space with a relatively downwards shift at the lower thoracic levels. The right sympathetic trunk is prone to have more communicating rami then the left. The lower levels of ganglia tend to have more normal rami. No clear pattern was found concerning the presence of the ascending rami and there was a decrease in the number of descending rami as the chain runs caudally. The intercostal rami remain a rare anatomical variation. CONCLUSIONS: This study presents an overview of the anatomy of the upper thoracic sympathetic chain. Its results may guide upper thoracic sympathectomy to improve clinical results. This review also provides a baseline for future studies on anatomical variations of the thoracic sympathetic trunk. More uniform reporting is necessary to compare different anatomical studies.

Segmental branches emanating from saphenous nerve morphing into sympathetic trunks for innervation of saphenous artery and its clinical implication for arterial sympathectomy.

Sympathectomy of arteries has been adopted for the treatment of peripheral arterial disease and Raynaud's disease. However, the exact route for sympathetic axons to reach peripheral arteries awaits further investigation that could pave the way for development of new surgical strategies. In this study, saphenous neurovascular bundles from 10 neonatal Sprague-Dawley rats first were harvested for whole-mount immunostaining to show sympathetic innervation pattern of the artery. Secondly, 40 Sprague-Dawley male rats weighing 350 to 400 g were assigned to five groups, receiving either sham, perivascular sympathectomy, nerve-artery separation, nerve transection in the saphenous neurovascular bundle, or lumbar sympathectomy surgery that removes the lumbar sympathetic trunks. Immediately after surgery, the arterial perfusion and diameter were measured using laser speckling contrast imaging, and 1 week later the saphenous neurovascular bundles were harvested for immunostaining using antibodies against TH, neuron-specific ß-tubulin (Tuj 1), and α-SMA to show the presence or absence of the TH-immuopositive staining in the adventitia. The differences among the five groups were determined using one-way analysis of variance (ANOVA). We found that an average of 2.8 ± 0.8 branches with a diameter of 4.8 ± 1.2 µm derived from the saphenous nerve that morphed into a primary and a secondary sympathetic trunk for innervation of the saphenous artery. Nerve-artery separation, nerve transection, and lumbar sympathectomy could eradicate TH-immunopositive staining of the artery, resulting, respectively, in a 12%, 36%, and 59% increase in diameter (P < .05), and a 52%, 63%, and 201% increase in perfusion compared with sham surgery (P < .01). In contrast, perivascular sympathectomy did not have a significant impact on the TH-immunopositive staining, the diameter, and perfusion of the distal part of the artery (P > .05). We conclude that the sympathetic innervation of an artery derives from segmental branches given off from its accompanying nerve. Nerve-artery disconnection is a theoretic option in sympathectomy of an artery.

Renal Denervation by Noninvasive Stereotactic Radiotherapy Induces Persistent Reduction of Sympathetic Activity in a Hypertensive Swine Model.

Background We have previously reported the feasibility of noninvasive stereotactic body radiotherapy (SBRT) as a novel approach for renal denervation. Methods and Results Herein, from a translational point of view, we assessed the antihypertensive effect and chronological evolution of SBRT-induced renal nerve injury within 6 months in a hypertensive swine model. Hypertension was induced in swine by subcutaneous implantation of deoxycorticosterone acetate pellets in combination with a high-salt diet. A single dose of 25 Gy with SBRT was delivered for renal denervation in 9 swine within 3.4±1.0 minutes. Blood pressure levels at baseline and 1 and 6 months post-SBRT were comparable to control (n=5), whereas renal norepinephrine was significantly lower at 6 months (P<0.05). Abdominal computed tomography, performed before euthanasia and renal function assessment, remained normal. Standard semiquantitative histological assessment showed that compared with control (1.4±0.4), renal nerve injury was greater at 1 month post-SBRT (2.3±0.3) and peaked at 6 months post-SBRT (3.2±0.8) (P<0.05), along with a higher proportion of active caspase-3-positive nerves (P<0.05). Moreover, SBRT resulted in continuous dysfunction of renal sympathetic nerves and low level of nerve regeneration in 6 months by immunohistochemistry analysis. Conclusions SBRT delivering 25 Gy for renal denervation was safe and related to sustained reduction of sympathetic activity by aggravating nerve damage and inhibiting nerve regeneration up to 6 months; however, its translation to clinical trial should be cautious because of the negative blood pressure response in the deoxycorticosterone acetate-salt hypertensive swine model.

Surgical Cardiac Sympathetic Denervation for Ventricular Arrhythmias: A Systematic Review.

Ventricular arrhythmias are potentially life-threatening disorders that are commonly treated with medications, catheter ablation and implantable cardioverter defibrillator (ICD). Adult patients who continue to be symptomatic, with frequent ventricular arrhythmia cardiac events or defibrillation from ICD despite medical treatment, are a challenging subgroup to manage. Surgical cardiac sympathetic denervation has emerged as a possible treatment option for people refractory to less invasive medical options. Recent treatment guidelines have recommendedcardiac sympathectomy for ventricular tachycardia (VT) or VT/fibrillation storm refractory to antiarrhythmic medications, long QT syndrome, and catecholaminergic polymorphic VT, with much of the data pertaining to pediatric literature. However, for the adult population, the disease indications, complications, and risks of cardiac sympathectomy are less understood, as are the most effective surgical cardiac denervation techniques for this patient demographic. This systematic review navigates available literature evaluating surgical denervation disease state indications, techniques, and sympathectomy risks for medically refractory ventricular arrhythmia in the adult patient population.

Renal Denervation in Hypertension.

The column in this issue is supplied by Drs. Benjamin Lee, MD, and Usman Ansari, DO. Dr. Lee is an assistant professor of clinical medicine at the Houston Methodist Institute for Academic Medicine and Weill Cornell Medical College. After earning his medical degree at Harvard Medical School, Dr. Lee completed a residency in internal medicine and a nephrology fellowship at the University of California San Francisco (UCSF) while simultaneously obtaining a master of advanced study in clinical research from the UCSF departments of Epidemiology and Biostatistics. He maintains his clinical practice with the Houston Kidney Consultants. Dr. Ansari earned a Doctor of Osteopathy from Touro University College of Osteopathic Medicine in California and is completing his internal medicine residency at Houston Methodist.

Changes in cardiac sympathetic nerve activity on 123 I-metaiodobenzylguanidine scintigraphy after MitraClip therapy.

AIMS: In patients with heart failure, over-activation of the cardiac sympathetic nerve (CSN) function is associated with severity of heart failure and worse outcome. The effects of MitraClip therapy on the CSN activity in patients with mitral regurgitation (MR) remained unknown. In this study, we evaluated the impact of the MitraClip therapy on CSN activity assessed by 123 I-metaiodobezylguanidine (MIBG) scintigraphy. METHODS AND RESULTS: We enrolled consecutive patients with moderate-to-severe (3+) or severe (4+) MR who were scheduled to undergo MitraClip procedure in this prospective observational study. MIBG scintigraphy was performed at baseline and 6 months after the MitraClip procedure to evaluate the heart-mediastinum ratio and washout rate (WR). Changes in these MIBG parameters were analysed. Of the 13 consecutive patients, 10 were successfully treated with MitraClip procedure and completed follow-up assessment. With regard to the MIBG parameters, changes in the early and delayed heart-mediastinum ratio from baseline to 6 months were not significant (2.16 ± 0.42 to 2.06 ± 0.34, P = 0.38 and 1.87 ± 0.39 to 1.83 ± 0.39, P = 0.43, respectively), whereas WR was significantly decreased (38.6 ± 3.9% to 32.6 ± 3.94%, P = 0.002). CONCLUSIONS: The CSN activity of the WR on MIBG imaging was improved 6 months after MitraClip therapy in patients with 3+ or 4+ MR.

Pulmonary artery denervation for pulmonary arterial hypertension.

Pulmonary arterial hypertension remains a progressive, life-limiting disease despite optimal medical therapy. Pulmonary artery denervation has arisen as a novel intervention in the treatment of pulmonary arterial hypertension, and other forms of pulmonary hypertension, with the aim of reducing the sympathetic activity of the pulmonary circulation. Pre-clinical studies and initial clinical trials have demonstrated that the technique can be performed safely with some positive effects on clinical, haemodynamic and echocardiographic markers of disease. The scope of the technique in current practice remains limited given the absence of well-designed, large-scale, international randomised controlled clinical trials. This review provides an overview of this exciting new treatment modality, including pathophysiology, technical innovations and recent trial results.

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk.

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-ß-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.

The involvement of renal afferents in the maintenance of cardiorenal diseases.

Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.