Article

Renal Sympathetic Denervation - A Review of Applications in Current Practice

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Abstract

Resistant hypertension is associated with high morbidity and mortality despite numerous pharmacological strategies. A wealth of preclinical and clinical data have demonstrated that resistant hypertension is associated with elevated renal and central sympathetic tone. The development of interventional therapies to modulate the sympathetic nervous system potentially represents a paradigm shift in the strategy for blood pressure control in this subset of patients. Initial first-in-man and pivotal, randomised controlled trials of endovascular, radio-frequency renal sympathetic denervation have spawned numerous iterations of similar technology, as well as many novel concepts for achieving effective renal sympatholysis. This review details the current knowledge of these devices and the evidence base behind each technology.

Disclosure:Vikas Kapil has received funding from the British Heart Foundation. Ajay K Jain is an Advisory board member for Medtronic Inc. Lobo received educational grant funding from Medtronic Inc., is a Consultant to and is on the speakers' bureau of St Jude Medical and is a Consultant to ROX Medical and Cardiosonic.

Received:

Accepted:

Correspondence Details:Melvin D Lobo, William Harvey Heart Centre, NIHR Cardiovascular Biomedical Research Unit, Centre for Clinical Pharmacology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ. E: m.d.lobo@qmul.ac.uk

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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Up to one-in-five treated hypertensive patients are deemed to be treatment resistant1-3 (on at least three different anti-hypertensive medication classes, including a diuretic)4-6 and have high cardiovascular risk.7-9 There is a paucity of high-quality evidence to suggest that the addition of a fourth line (or fifth, sixth line, etc.) medication is likely to bring either hypertension under control or to reduce excess morbidity/mortality in resistant hypertension (RHTN).5 Recently, renal sympathetic denervation (RSD) has been suggested as an effective, evidence-based approach for controlling RHTN.10

The Rationale for Renal Sympathetic Denervation in Human Resistant Hypertension
Activation of the sympathetic nervous system (SNS) is now recognised to occur in all stages of hypertension and correlates to the severity of hypertension.11,12 The renal efferent and afferent SNS neural fibres make their own contribution to the maintenance of the hypertensive phenotype. Renal SNS afferents run along the renal artery adventitia and cluster in the renal pelvis13,14 and activity of these renal SNS fibres regulate whole body sympathetic tone by moderating hypothalamic activity.15 Renal SNS efferents innervate the kidneys from the paravertebral ganglia at T10-L2 and also run alongside the renal afferents in the renal artery adventitia.13 Renal SNS efferent activity mediates renal sodium retention, volume expansion16 and stimulates the neuro-humoral renin-angiotensin-aldosterone axis, further elevating blood pressure (BP) though salt/water retention and vasoconstriction.17

In the first half of the 20th century, surgical thoracolumbar sympathectomy (resulting in renal sympathectomy) was performed to treat malignant hypertension with good results in terms of reducing both BP and mortality.18,19 However, this radical surgical operation was not without significant operative mortality and post-operative morbidity, including postural hypotension, erectile dysfunction and syncope.

Thus the procedure fell out of favour with the advent of antihypertensive medications that were non-invasive, tolerable and proved to reduce BP and mortality.20

Preclinical studies have clearly demonstrated that interruption of renal SNS signalling, by either surgical ligation and re-anastomosis or chemical adventitial stripping of the renal artery, prevents the development of hypertension and, furthermore, attenuates established hypertension in numerous animal models of hypertension.21 Further evidence for benefit of renal sympathectomy in the treatment of hypertension comes from a study of patients treated with bilateral nephrectomy for end-stage chronic kidney disease (CKD) maintained on haemodialysis or post-transplantation, which demonstrates sustained BP reduction.22 While these techniques are not suitable for use in humans, the recent development of minimally invasive, catheter-based solutions10,23 to effect selective RSD has re-ignited interest in this field.

Figure 1: Current Renal Sympathetic Denervation Technologies
Current Technologies for Renal Sympathetic Denervation
The paradigm for a technology that may have utility in renal SNS modulation for hypertension is that it achieves selective RSD with no collateral damage to adjacent/other structures. The different technologies that are currently being tested in both preclinical and clinical studies vary in their potential benefits and pitfalls and these issues are discussed below.

Radio-frequency Neural Ablation
Radio-frequency (RF) energy, introduced for ablation of neurovascular tissue more than 25 years ago,24 is an alternating electrical current that produces tissue destruction by both direct resistive heating of the tissue in contact with the catheter tip and by thermal conduction to deeper tissue. The RF electrical current is delivered most frequently in the unipolar mode, with completion of the electrical circuit via another electrode placed on the skin. In bipolar mode, two closely opposed electrodes are placed on the catheter electrode tip. On energy delivery to the target surface, the catheter tip heats subjacent (up to 4 mm) tissues from 50 to 70°C.25 A sudden rise in impedance can suggest over-heating and charring of tissue at the tip and many modern RF catheters are designed with auto-feedback mechanisms to prevent excessive temperature elevations. Other factors that influence tissue destruction include duration of energy application, with at least 35 seconds required for uniform temperature elevations in targeted tissue,26 catheter electrode size and tissue apposition and the level of power applied from the RF generator.

Anatomical considerations are required before progressing to RF RSD.27-29 Prior renal artery duplex scanning or cross-sectional imaging to rule out significant renal atherosclerotic disease is required, and this is confirmed at the time of endovascular RSD by formal angiography before ablation catheter placement. The main trunk diameter should be >4 mm and the length should be >20 mm to allow both effective blood flow for cooling (see below) and sufficient space for multiple ablations. Furthermore, accessory or dual arteries should be of similar dimensions to allow treatment to be given to all arteries concurrently. To date, RF RSD is not recommended in patients with previous renal artery angioplasty or endovascular stents to treat previous atherosclerotic renal artery stenosis (RAS).

First-generation RF RSD systems utilise flexible RF catheters that are advanced into each renal artery in turn under fluoroscopic guidance. Energy delivery causes thermal destruction of SNS neural tissue in the perivascular adventitia and using native renal blood flow to cool the intima, endothelial damage is reduced. Intra-procedural utilisation of vasodilators, such as nitroglycerine (glyceryl trinitrate) and non-dihydropyridine calcium channel blockers, are often used to prevent vasospasm that may accompany energy delivery. The perivascular neural bundle also contains sensory C fibres and thus neural destruction is accompanied by significant pain, necessitating conscious sedation and adequate opiate-based analgesia.

Ardian Inc. (later purchased by Medtronic Inc.) developed the first minimally invasive technology to effect selective RSD. The Symplicity™ (Minneapolis, US) catheter consists of a unipolar ablation catheter and a proprietary low-energy RF generator, and is the most widely used and studied device to date. Typically four to seven ablations (5 mm apart; 2 minutes per ablation) are performed sequentially in each artery in a classic helical pattern distally to proximally to prevent potential RAS and cover the full arterial circumference.

Symplicity HTN-1 was a non-randomised, first proof-of-concept study using the Symplicity system in severe RHTN (n=45; office BP=177/101 mmHg; mean anti-hypertensive medications=4.7) demonstrating improvement of office BP by 27/17 mmHg at 12-months10 and by 32/14 mmHg at 36 months.30 Symplicity HTN-2 was a randomised trial of RSD (using the Symplicity catheter) plus current treatment versus current treatment only. In patients randomised to RSD (n=49; office BP=178/97 mmHg; mean anti-hypertensive medications=5.2), 6-month office BP-lowering was 32/12 mmHg compared with 1/0 mmHg in controls (n=51).31

Since the publication of these initial studies using the Symplicity catheter, other devices have quickly come to the market and tried to establish their own safety and efficacy profiles (see Figure 1; Tables 1-3), with improved technological iterations on the original Ardian Inc. design. Recently, the first dedicated radial-approach RSD device has gained a CE mark (Iberis™, Terumo Corp, Tokyo, Japan) (see Table 1). This is a unipolar electrode similar to the Symplicity system that is introduced via the trans-radial approach rather than the trans-femoral approach. This trans-radial approach has been shown to be associated with reduced access-site complications in percutaneous coronary interventions (PCI) and is recommended as the default site for access in PCI.32

Table 1: Radiofrequency Technologies for Renal Sympathetic Denervation
Table 1: Radiofrequency Technologies for Renal Sympathetic Denervation

Several companies have designed multi-electrode or elongated, spiral electrode catheters, including a second-generation catheter from Medtronic Inc., which can produce simultaneous energy applications at multiple anatomical sites within the renal artery, either mounted externally on a scaffold or inflatable balloon (see Table 1). Not only does this substantially reduce procedure time and contrast load but it may also help achieve complete circumferential nerve ablation, as the catheter does not need to be re-positioned between energy applications. Even more recently, 3D electrical current mapping technology, commonly applied in cardiac electrophysiology (EP) procedures, has been used to further reduce both contrast load and radiation exposure.33

Further iterations of RF RSD devices include integrated cooling mechanisms to prevent local tissue heating to excessive levels (see Table 1). First-generation systems have utilised concurrent renal artery blood flow to aid cooling of the endothelium to prevent thermal damage. Computational modelling has recently indicated that the intrinsic rate of renal artery blood flow, which cannot be easily manipulated peri-procedurally, is crucial in controlling both the direct, local (i.e. thermal effects to arterial wall) and distant (i.e. thermal effect on blood) effects of RF RSD.34 To counteract these effects, saline-irrigated RF catheters have become a standard design for cardiac EP ablations and have been shown to reduce contact-tissue heating without reducing the destruction of deep target tissue.35 Preliminary preclinical data in swine suggest that irrigated RF RSD ablation using the ThermoCOOL™ system (Biosense Webster Inc. [Diamond Bar, US] [see Table 1]) reduced arterial media and peri-arterial collagen damage but produced similar neural destruction compared with non-irrigated RF RSD procedures in arteries harvested 10 days post-procedure.36

Endothelial damage is a serious concern with non-irrigated RF RSD devices as it has been demonstrated with the use of optical coherence tomography (OCT) imaging that first-generation RF RSD catheters (Symplicity and EnligHTN™ [St Jude Medical, St Paul, US] systems) caused diffuse renal artery vasospasm, local tissue oedema and thrombus,37,38 suggesting the potential need for concurrent, periprocedural anti-platelet therapy.37 This may well be a temporary phenomenon and the clinical significance of these imaging findings is not currently known. Reassuringly, preclinical porcine studies using the Symplicity catheter showed no significant RAS, smooth muscle hyperplasia or thrombosis angiographically or histologically at 6 months post RF RSD.23 Follow-up renal imaging in the Symplicity trials has indicated only one novel RAS as a sequela of RF RSD in 88 patients followed for up to 3 years.30 Furthermore, renal safety has recently been explored in 15 patients with RHTN and moderate to severe CKD stages 3-4) that would have been excluded from the Symplicity HTN-1 and HTN-2 trials. This study revealed preservation of renal function to 12 months after RSD,39 which provides limited but further encouraging data regarding renal safety.

The potential damage caused by RF energy application direct to the renal artery endothelium means that it may not be the optimal technology for endovascular RSD. Other non-RF technologies, described below, are being developed to overcome some of these concerns. Interestingly, the proximity of the renal nerves to the renal pelvis has led to the development of a non-endovascular approach to RF-mediated RSD. Verve Medical (Santa Barbara, US) have developed an eponymous, retro-ureteric delivered RF device that has been tested in preclinical porcine studies, with reduction in renal tissue norepinephrine (NE) levels and no significant vascular or renal parenchymal damage up to 30 days post-procedure.40 This approach prevents patient exclusion for renal arterial anatomical reasons that was common in the Symplicity RSD clinical studies,10,31 but other urological pathologies may prevent usage of this approach in certain patients.

Ultrasound Neural Ablation
Ultrasound (US) energy delivers sound waves >20 Hz. When US is directed against a medium that is able to absorb the energy, it is converted to thermal energy within that medium. It can be delivered without vessel contact, with US waves passing through fluid/interposing tissue to heat target tissue to generate targeted thermal injury. It has been established as an effective therapy for cardiac EP procedures.41 Different approaches have been developed to harness the potential utility of US for RSD with the proposed benefits over RF ablation being controlled and greater depth of denervation and endothelial sparing (see Table 2). The requisite depth for effective denervation is, however, debatable as the majority of human SNS fibres have been shown to lie within 2 mm of the renal arterial lumen14 and deeper denervation techniques may pose harm to adjacent structures including the psoas muscle (posteriorly) and bowel within the peritoneal space (anteriorly).

While extra-corporeal high-intensity focused US (HIFU) has long been used to ablate deep, solid tissue tumours through thermal injury42 and has recently been tested in preclinical canine studies of RSD,43 the use of extra-corporeal, low-intensity focused US (LIFU) for RSD represents an entirely unique and potentially non-invasive strategy that is particularly attractive (see Table 2). The mechanism of tissue damage by LIFU is not entirely characterised and is thought to be predominantly sono-mechanical (i.e. vibration-induced cellular damage) rather than thermal.44 Although the Surround Sound™ system from Kona Medical (Campbell, US) is currently using a targeting catheter in its early phase development, the stated aim of the company is to develop a fully non-invasive technology that applies LIFU without the requirement for endovascular access. One could imagine such a technology being easily translatable to an ambulant patient setting, which would be the Holy Grail of RHTN therapy.

Table 2: Ultrasound Technologies for Renal Sympathetic Denervation
Table 2: Ultrasound Technologies for Renal Sympathetic Denervation
Table 3. Chemical Technologies for Renal Sympathetic Denervation
Table 3. Chemical Technologies for Renal Sympathetic Denervation
Chemical Neural Ablation
Therapeutic pharmacological neurolysis has been recognised for over a century and several pharmacological agents are being developed for RSD (see Table 3). Targeted drug delivery is an attractive method offering selective neurolysis and obviating endothelial and deeper vascular damage. Alcohol is an effective neurolytic,45 previously used for trigeminal neuralgia,46 and, in fact, more than 20 years ago47 to treat renovascular hypertension through percutaneous injection into the renal artery adventitia. Botulinum toxin type A (commonly known as Botox®) or type B are responsible for the flaccid paralysis associated with Clostridium botulinum poisoning, and have been developed as therapeutic neurolytics to treat muscular dystonias48 and spasticity.49 Similar neurotoxins have been packaged in magnetic nanoparticles that provide a mechanism for targeted drug delivery when combined with an external magnetic field, and have been successfully applied to cardiac SNS ganglionic plexi to treat atrial fibrillation.50 Guanethidine, one of the first anti-hypertensive medications, reduces norepinephrine (NE) levels in pre-synaptic nerve terminals. At higher systemic doses it has been shown to cause selective SNS neurolysis51 through an immune-mediated mechanism.52 The anti-neoplastic vinca alkaloid, vincristine, is well recognised to be neurotoxic, especially to peripheral nerves with systemic application,53 and while this can cause disabling peripheral neuropathies in cancer patients, this medication has been re-tasked for therapeutic usage as an RSD agent, and is the only chemicalbased RSD technology that has produced both preclinical and firstin- man data in peer-reviewed publications.54-56

Cryoablation to Achieve Renal Sympathetic Denervation
Cryotherapy, an effective ablation technology, cools target tissue to ≤40°C, which results in intra-cellular ice crystal formation and cell death57 and has been used to destroy non-epithelial tissue for over 50 years.58 Cryoablation has become a mainstay for cardiac EP studies, as there is a reduced frequency of vascular complications59 and reduced pain60 compared with standard RF techniques. Standard cardiac EP cryoablation catheters have been used to determine the safety of this approach in preclinical studies that demonstrated effective RSD with no macroscopic evidence of endovascular thrombi, renal parenchymal or vascular damage and endothelial cell preservation by immunohistochemistry.61 In a small pilot study in patients with RHTN deemed non-responders to RF RSD, cryoablation caused appreciable BP reductions in all three patients to 6 months post-procedure (>22/4 mmHg ambulatory BP).62 This approach is being developed by commercial ventures, including CryoMend Inc. and Cryomedix Inc. (both San Diego, US) although there have been no preclinical or clinical data outputs to date. It is too early to speculate on the long-term potential for cryoablation in RSD and on a cautionary note, higher rates of recurrence after successful index ablation are apparent for certain cardiac arrhythmias compared with RF ablation.60

Ionising Radiation Neural Ablation
Radio-ablation is also being developed for endovascular RSD. Although peripheral nerves were initially thought to be relatively radio-resistant, it was established more than 50 years ago that ionising radiation induced neural fibrosis and myelin loss, leading to symptomatic neuropathies in cancer patients treated with radiotherapy.63 Novel, radiation-based therapies that are being developed for RSD include endovascular β-radiation brachytherapy (25-50 Gy delivered by Best Vascular Inc., [Springfield, Virginia] Novoste™ Beta-Cath™ catheter), which has demonstrated effective neural destruction and renal artery safety at 25-50 Gy in swine (n=10) up to 2 months post-procedure,64 and stereotactic, non-invasive, robot-assisted, X-radiation radiosurgery (Cyberheart Inc., [Sunnyvale, US] Cyberheart system™), based on the same company's Cyberknife™ system, used to treat solid organ tumours. No preclinical data have been presented to date.

Current Controversies and Future Opportunities
Technical Failure versus Non-responder
One of the main problems with current application of all RSD technologies is the inability to separate technical failure of the procedure from lack of response of patients to effective RSD. This latter problem could arise because either that renal SNS signalling is not paramount to RHTN in that patient (i.e. other mechanisms are driving the RHTN phenotype) or that the patient's anatomy/ physiology is unable to respond to the reduction in SNS signalling (i.e. large vessel stiffening). Furthermore, a purported cumulative effect to RF RSD in terms of BP lowering over 3 years30 may mean that early lack of BP lowering does not reflect lack of either procedural success or response to RSD. This would seriously complicate decision-making regarding 're-do' procedures (clinicaltrials.gov: NCT01834118) or proceeding to other interventional technologies, such as baroreflex activation therapy (BAT)65,66 or arterio-venous coupling,67 in early non-responders to RSD.68 Furthermore, the recent announcement of the failure of Symplicity HTN-3 to meet its primary efficacy end-point at 6 months with a first-generation sequential ablation catheter system may reflect difficulties in demonstrating effective neural destruction, a primary end-point that was too early in the natural history of the response to RSD, effective guidelinedriven treatment of RHTN in the placebo-sham arm or that RF RSD was truly ineffective in BP lowering in a cohort of patients that had true RHTN in and out of office.

Further research to determine which patients are suitable/likely to respond to RSD is essential. To date, only baseline BP correlates to the magnitude of BP response to RF RSD across multiple cohorts.10,30,31,69,70 Single-unit muscle sympathetic nerve activity is reduced within 3 months of RF RSD and may predict future BP response but this is not established yet.71 Impaired cardiac baroreflex sensitivity predicts BP response to,72 and improves after,73 RF RSD.

More recently, intra-arterial BP response to high-frequency stimulation ([HFS] 20 Hz for 10 seconds) at the renal artery ostium immediately post procedure suggests a potential test of procedural efficacy.74 In this study, HFS pre-procedure caused an immediate >15 mmHg increase in BP in all patients that was almost entirely blunted (<6 mmHg) post RF RSD.74 Other investigations that have been utilised in subsets of patients include renal NE spillover10 and single-unit muscle sympathetic nerve activity.71 However, both techniques are time consuming, require invasive testing preand post-procedure and are currently only available in specialist centres with expertise of autonomic function assessment. These concerns highlight the growing importance of collaboration with autonomic neurophysiologists and cardiovascular physiologists to develop the means to accurately phenotype individual patients with respect to the role of the SNS and its many subdivisions in their hypertension. In a similar fashion, the clinician already subjects patients to detailed biochemical and imaging characterisation as a pre-requisite to adrenalectomy for patients with adrenal nodules. Why then should (expensive and invasive) RSD be offered to all patients with RHTN without first determining the involvement of their renal SNS?

Clinical Trials Inadequacies
Criticisms of published RSD clinical trials have been widely propagated75-78 and include lack of sham control; non-blinded design; no per protocol exclusion of both secondary causes of hypertension and non-adherence to therapy; intermediate soft end-points (often 6 month office BP); and lack of ambulatory BP use as standard for both inclusion to exclude white coat effect, and also as a BP outcome and lack of durability and safety beyond 3 years. Ambulatory BP has been included in more recent small studies in moderate RHTN,79,80 and both sham control (clinicaltrials.gov: NCT01418261) and major adverse cardiovascular events as primary end-points (clinicaltrials.gov: NCT01903187) are included in current large international studies but the results from these studies will not be known for many years, so the current use of RSD technologies is based on low numbers of non-high-quality studies. Durability of BP lowering has recently been demonstrated for at least 3 years,30 but concerns about renal nerve regrowth remain81 although the potential impact of any re-innervation on BP is unclear.30 Reassuringly, denervated renal transplants have preserved functions of solute clearance, electrolyte transport and hormonal function82 and RF RSD in moderate to severe CKD is both effective and safe up to 1 year post procedure.39

What is the Best Renal Sympathetic Denervation System?
Currently it is difficult to recommend one RSD technology above and beyond any other, as there are no head-to-head comparisons of intra- or inter-class RSD technologies. The majority of clinical trial experience is with the first-generation RF Symplicity catheter, though as outlined previously methodological and technological advances in second-generation RF and other non-RF systems give theoretical preference to more recent iterations. A clinical study of four RSD technologies, including one single electrode RF system, two multi-electrode systems and one non-RF system, may help answer this question with respect to BP lowering and procedural and renal artery safety (clinicaltrials.gov: NCT01888315). Notably, it remains unproven whether any technological form of RSD is equivalent (or superior) to guideline-driven pharmacological management of RHTN5 and specific trials of this type are not currently under way. Until this is the case, RSD should remain a treatment of last resort for RHTN.

Conclusion
To date, the majority of clinical studies have evaluated the efficacy of RF (and non-RF) RSD in predominantly severe RHTN. However, given that the pathophysiological basis for RSD therapy is based not on BP level but on the recognition that RHTN is associated with elevated central SNS tone, RSD may be an effective treatment for other conditions that exhibit similar elevated central SNS tone, whether renally mediated or not. As such, RF RSD has been evaluated in other systemic conditions and pleiotropic effects of RF RSD have been reported in both systolic83 and diastolic84 heart failure, obstructive sleep apnoea,85 glycaemic control in RHTN patients85,86 and both supra-ventricular74 and ventricular arrhythmias.87

With the proliferation of different technologies and devices for RSD, much more rigorous research is required so that clinicians can confidently and fully inform patients with RHTN which is the most efficacious and safe intervention for them, taking into account the individual pathophysiological basis for RHTN and matching that to available technologies or not as is appropriate. The principles that should guide development of and selection of appropriate RSD technologies should include: minimally/entirely non-invasive device; predictability of injury pattern; selectivity for renal nerves; permanent nerve destruction; minimal injury to renal artery and collateral structures; minimal procedural pain; short procedure time; durable modulation of central SNS tone; and BP lowering. The publication of the Simplicity HTN-3 dataset is now critical so that the full implications of this disappointing result can further inform the most appropriate use of this technology and treatment for RHTN and potentially other disorders as well. The hypertension specialist, and patients, should welcome this paradigm shift in the landscape for treatment of RHTN but a cautious approach should be maintained with newer, novel technologies until evidence emerges to support their use.

References

  1. de la Sierra A, Segura J, Banegas JR, et al., Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring, Hypertension, 2011;57:898-902.
    Crossref | PubMed
  2. Persell SD, Prevalence of resistant hypertension in the United States, 2003-2008, Hypertension, 2011;57:1076-80.
    Crossref | PubMed
  3. Pimenta E, Calhoun DA, Resistant hypertension: incidence, prevalence, and prognosis, Circulation, 2012;125:1594-6.
    Crossref | PubMed
  4. Mancia G, Fagard R, Narkiewicz K, et al., 2013 ESH/ESC Guidelines for the management of arterial hypertension:The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), Eur Heart J,
    2013;34:2159-2219.
    Crossref | PubMed
  5. National Institute of Clinical Excellence. Hypertension: Clinical Management of Primary Hypertension in Adults. London:Royal College of Physicians, 2011.
    Crossref | PubMed
  6. Calhoun DA, Jones D, Textor S, et al., Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research, Hypertension, 2008;51:1403-19.
    Crossref | PubMed
  7. Daugherty SL, Powers JD, Magid DJ, et al., Incidence and prognosis of resistant hypertension in hypertensive patients, Circulation,2012;125:1635-42.
    Crossref | PubMed
  8. Kumbhani DJ, Steg PG, Cannon CP, et al., Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis, Eur Heart J, 2013;34:1204-14.
    Crossref | PubMed
  9. Pierdomenico SD, Lapenna D, Bucci A, et al., Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and  true resistant hypertension, Am J Hyp, 2005;18:1422-8.
    Crossref | PubMed
  10. Krum H, Schlaich M, Whitbourn R, et al., Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study, Lancet, 2009;373:1275-81.
    Crossref | PubMed
  11. Grassi G, Cattaneo BM, Seravalle G, et al., Baroreflex control of sympathetic nerve activity in essential and secondary hypertension, Hypertension, 1998;31:68-72.
    Crossref | PubMed
  12. Esler M, Lambert G, Jennings G, Regional norepinephrine turnover in human hypertension, Clin Exp Hypertens A, 1989;11 Suppl. 1:75-89.
    Crossref | PubMed
  13. Barajas L, Liu L, Powers K, Anatomy of the renal innervation: intrarenal aspects and ganglia of origin, Can J Physiol Pharmacol, 1992;70:735-49.
    Crossref | PubMed
  14. Atherton DS, Deep NL, Mendelsohn FO, Micro-anatomy of the renal sympathetic nervous system: a human postmortem histologic study, Clin Anat, 2012;25:628-33.
    Crossref | PubMed
  15. Stella A, Zanchetti A, Functional role of renal afferents, Physiol Rev, 1991;71:659-82.
    PubMed
  16. Prosnitz EH, DiBona GF, Effect of decreased renal sympathetic nerve activity on renal tubular sodium reabsorption, Am J Physiol, 1978;235:F557-63.
    PubMed
  17. Zimmerman BG, Sybertz EJ, Wong PC, Interaction between sympathetic and renin-angiotensin system, J Hypertens, 1984;2:581-7.
    Crossref | PubMed
  18. Parkes WE, Thoracolumbar sympathectomy in hypertension, Br Heart J, 1958;20:249-52.
    Crossref | PubMed
  19. Smithwick RH, Thompson JE, Splanchnicectomy for essential hypertension; results in 1,266 cases, JAMA, 1953;152:1501-4.
    Crossref | PubMed
  20. Veterans Administration Cooperative Study Group, Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg, JAMA, 1967;202:1028-34.
    Crossref | PubMed
  21. DiBona GF, Kopp UC. Neural control of renal function, Physiol Rev, 1997;77:75-197. vOnesti G, Kim KE, Greco JA, et al., Blood pressure regulation
    in end-stage renal disease and anephric man, Circ Res, 1975;36:145-52.
    Crossref | PubMed
  22. Rippy MK, Zarins D, Barman NC, et al., Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety, Clin Res Cardiol, 2011;100:1095-1101.
    Crossref | PubMed
  23. Huang SK, Bharati S, Graham AR, et al., Closed chest catheter desiccation of the atrioventricular junction using radiofrequency energy - a new method of catheter ablation, J Am Coll Cardiol, 1987;9:349-58.
    Crossref | PubMed
  24. Haines DE, The biophysics of radiofrequency catheter ablation in the heart: the importance of temperature monitoring, Pacing Clin Electrophysiol, 1993;16:586-91.
    Crossref | PubMed
  25. Wittkampf FH, Simmers TA, Hauer RN, et al., Myocardial temperature response during radiofrequency catheter ablation, Pacing Clin Electrophysiol, 1995;18:307-17.
    Crossref | PubMed
  26. Schlaich MP, Schmieder RE, Bakris G, et al., International expert consensus statement: Percutaneous transluminal renal denervation for the  treatment of resistant hypertension, J Am Coll Cardiol, 2013;62(22):2031-45.
    Crossref | PubMed
  27. Caulfield MJ, de Belder M, Cleveland T, et al., The Joint UK Societies' consensus statement on renal denervation for resistant hypertension, British  Hypertension Society, 2012. Available at: http://www.bcs.com/pages/news_full. asp?NewsID=19792021 (accessed 24 February 2014).
  28. Schmieder RE, Redon J, Grassi G, et al., ESH position paper: renal denervation - an interventional therapy of resistant hypertension, J Hypertens, 2012;30:837-41.
    Crossref | PubMed
  29. Krum H, Schlaich MP, B├Âhm M, et al., Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study, Lancet, 2014;383(9917):622-9.
    Crossref | PubMed
  30. Symplicity HTN-2 Investigators, Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a  randomised controlled trial, Lancet, 2010;376:1903-9.
    Crossref | PubMed
  31. Hamon M, Pristipino C, Di Mario C, et al., Consensus document on the radial approach in percutaneous cardiovascular interventions: position paper by the European Association of Percutaneous Cardiovascular Interventions and Working Groups on Acute Cardiac Care and Thrombosis of the  European Society of Cardiology, EuroIntervention, 2013;8:1242-51.
    Crossref | PubMed
  32. Zaman S, Pouliopoulos J, Al Raisi S, et al., Novel use of NavX three-dimensional mapping to guide renal artery denervation, EuroIntervention, 2013;9:687-93.
    Crossref | PubMed
  33. Guo X, Zhai F, Nan Q, The temperature field simulation of radiofrequency catheter-based renal sympathetic denervation for resistant hypertension,  Biomed Mater Eng, 2014;24:315-21.
    PubMed
  34. Nakagawa H, Yamanashi WS, Pitha JV, et al., Comparison of in vivo tissue temperature profile and lesion geometry for radiofrequency ablation with a saline-irrigated electrode versus temperature control in a canine thigh muscle preparation, Circulation, 1995;91:2264-73.
    Crossref | PubMed
  35. Sakakura K, Ladich E, Fuimaono K, et al., Comparison of arterial, surrounding soft tissue and nerve damage with irrigated vs. non-irrigated  radiofrequency ablation [abstract], J Am Coll Cardiol, 2013;62:B149-50.
    Crossref
  36. Templin C, Jaguszewski M, Ghadri JR, et al., Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the Simplicity(R) catheter system and the EnligHTN™ multi-electrode renal denervation catheter,  Eur Heart J, 2013;34:2141-8.
    Crossref
  37. Cook S, Goy J-J, Togni M, Optical coherence tomography findings in renal denervation, Eur Heart J, 2012;33:2992.
    Crossref | PubMed
  38. Hering D, Mahfoud F, Walton AS, et al., Renal denervation in moderate to severe CKD, J Am Soc Nephrol, 2012;23:1250-7.
    Crossref | PubMed
  39. Heuser RR, Mhatre AU, Buelna TJ, et al., A novel non-vascular system to treat resistant hypertension, EuroIntervention, 2013;9:135-9.
    Crossref | PubMed
  40. Natale A, Pisano E, Shewchik J, et al., First human experience with pulmonary vein isolation using a through-the-balloon circumferential ultrasound ablation system for recurrent atrial fibrillation, Circulation, 2000;102:1879-82.
    Crossref | PubMed
  41. Kennedy JE, High-intensity focused ultrasound in the treatment of solid tumours, Nat Rev Cancer, 2005;5:321-7.
    Crossref | PubMed
  42. Wang Q, Guo R, Rong S, et al., Noninvasive renal sympathetic denervation by extracorporeal high-intensity focused ultrasound in a pre-clinical canine model, J Am Coll Cardiol, 2013;61:2185-92.
    Crossref | PubMed
  43. Feril LB, Kondo T, Biological effects of low intensity ultrasound: the mechanism involved, and its implications on therapy and on biosafety of ultrasound, J Radiat Res, 2004;45:479-89.
    Crossref | PubMed
  44. May O, The functional and histological effects of intraneural and intraganglionic injections of alcohol, Br Med J, 1912;2:465-170.
    Crossref | PubMed
  45. Harris W, Alcohol injection of the Gasserian ganglion for trigeminal neuralgia, Lancet, 1912;179:218-21.
    Crossref | PubMed
  46. Iaccarino V, Russo D, Niola R, et al., Total or partial percutaneous renal ablation in the treatment of renovascular hypertension: radiological and clinical aspects, Br J Radiol, 1989;62:593-8.
    Crossref | PubMed
  47. Jankovic J, Orman J, Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study, Neurology, 1987;37:616-23.
    Crossref | PubMed
  48. Das TK, Park DM, Effect of treatment with botulinum toxin on spasticity, Postgrad Med J, 1989;65:208-10.
    Crossref | PubMed
  49. Yu L, Scherlag BJ, Dormer K, et al., Autonomic denervation with magnetic nanoparticles, Circulation, 2010;122:2653-9.
    Crossref | PubMed
  50. Burnstock G, Evans B, Gannon BJ, et al., A new method of destroying adrenergic nerves in adult animals using guanethidine, Br J Pharmacol, 1971;43:295-301.
    PubMed
  51. Manning PT, Powers CW, Schmidt RE, et al., Guanethidineinduced destruction of peripheral sympathetic neurons occurs by an immune-mediated mechanism, J Neurosci, 1983;3:714-24.
    Crossref | PubMed
  52. Casey EB, Jellife AM, Le Quesne PM, et al., Vincristine neuropathy. Clinical and electrophysiological observations, Brain, 1973;96:69-86.
    Crossref | PubMed
  53. Stefanadis C, Synetos A, Toutouzas K, et al., New double balloon delivery catheter for chemical denervation of the renal artery with vincristine, Int J Cardiol, 2013;168:4346-8.
    Crossref | PubMed
  54. Stefanadis C, Toutouzas K, Synetos A, et al., Chemical denervation of the renal artery by vincristine in swine. A new Renal Sympathetic Denervation - A Review of Applications in Current Practice INTERVENTIONAL CARDIOLOGY REVIEW 61 catheter based technique, Int J Cardiol, 2013;167:421-5.
    Crossref | PubMed
  55. Stefanadis C, Toutouzas K, Vlachopoulos C, et al., Chemical denervation of the renal artery with vincristine for the treatment of resistant arterial  hypertension: first-in-man application, Hellenic J Cardiol, 2013;54:318-21.
    PubMed
  56. Heard BE, Nuclear crystals in slowly frozen tissues at very low temperatures; comparison of normal and ascites tumour cells, Br J Surg, 1955;42:659-63.
    Crossref | PubMed
  57. Cooper IS, Cryogenic surgery: a new method of destruction or extirpation of benign or malignant tissues, N Engl J Med, 1963;89:741-749.
    Crossref
  58. Tse H-F, Reek S, Timmermans C, et al., Pulmonary vein isolation using transvenous catheter cryoablation for treatment of atrial fibrillation without risk of pulmonary vein stenosis, J Am Coll Cardiol, 2003;42:752-8.
    Crossref | PubMed
  59. Deisenhofer I, Zrenner B, Yin Yh, et al., Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the CYRANO Study): results from a large multicenter prospective randomized trial, Circulation, 2010;122:2239-45.
    Crossref | PubMed
  60. Prochnau D, Figulla HR, Romeike BFM, et al., Percutaneous catheter-based cryoablation of the renal artery is effective for sympathetic denervation in a sheep model, Int J Cardiol, 2011;152:268-70.
    Crossref | PubMed
  61. Prochnau D, Figulla HR, Surber R, Cryoenergy is effective in the treatment of resistant hypertension in nonresponders to radiofrequency renal  denervation, Int J Cardiol, 2013;167:588-90.
    Crossref | PubMed
  62. Stoll BA, Andrews JT, Radiation-induced peripheral neuropathy, Br Med J, 1966;1:834-7.
    Crossref | PubMed
  63. Waksman R, Barbash IM, Chan R, et al., Beta radiation for renal nerve denervation: initial feasibility and safety, EuroIntervention, 2013;9:738-44.
    PubMed
  64. Bakris GL, Nadim MK, Haller H, et al., Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial, J Am Soc Hypertens, 2012;6:152-8.
    Crossref | PubMed
  65. Hoppe UC, Brandt MC, Wachter R, et al., Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with  pacemaker-like safety profile: results from the Barostim Neo trial, J Am Soc Hypertens, 2012;6:270-6.
    Crossref | PubMed
  66. Brouwers S, Dolan E, Galvin J, et al., Creation of an iliofemoral arteriovenous fistula in patients with severe hypertension: a prospective open label multi center pilot study [abstract], J Hypertens, 2013;31:e103.
  67. Ukena C, Cremers B, Ewen S, et al., Response and nonresponse to renal denervation: who is the ideal candidate?, EuroIntervention, 2013;9 Suppl. R:R54-7.
    Crossref | PubMed
  68. Persu A, Jin Y, Azizi M, et al., Blood pressure changes after renal denervation at 10 European expert centers, J Hum Hypertens, 2014;28(3):150-6.
    Crossref | PubMed
  69. Worthley SG, Tsioufis CP, Worthley MI, et al., Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant  hypertension: the EnligHTN I trial, Eur Heart J, 2013;34:2132-40.
    Crossref | PubMed
  70. Hering D, Lambert EA, Marusic P, et al., Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant  hypertension, Hypertension, 2013;61:457-64.
    Crossref | PubMed
  71. Zuern CS, Eick C, Rizas KD, et al., Impaired cardiac baroreflex sensitivity predicts response to renal sympathetic denervation in patients with  resistant hypertension, J Am Coll Cardiol, 2013;62(22):2124-30.
    Crossref | PubMed
  72. Hart EC, McBryde FD, Burchell AE, et al., Translational examination of changes in baroreflex function after renal denervation in hypertensive rats and  humans, Hypertension, 2013;62:533-41.
    Crossref | PubMed
  73. Pokushalov E, Romanov A, Corbucci G, et al., A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension, J Am Coll Cardiol, 2012;60:1163-70.
    Crossref | PubMed
  74. Jin Y, Thijs L, Persu A, et al., Letter to the Editor: no support for renal denervation in a meta-analysis, J Am Coll Cardiol, 2013;62:2029-30.
    Crossref | PubMed
  75. Persu A, Renkin J, Thijs L, et al., Renal denervation: ultima ratio or standard in treatment-resistant hypertension, Hypertension, 2012;60:596-606.
    Crossref | PubMed
  76. Staessen JA, Jin Y, Thijs L, et al., First-in-man randomized clinical trial of renal denervation for atrial arrhythmia raises concern, J Am Coll Cardiol, 2013;62:e445-6.
    Crossref | PubMed
  77. Howard JP, Nowbar AN, Francis DP, Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug  trials of 4121 patients with focus on trial design: the CONVERGE report, Heart, 2013;99:1579-87.
    Crossref | PubMed
  78. Kaltenbach B, Franke J, Bertog SC, et al., Renal sympathetic denervation as second-line therapy in mild resistant hypertension: a pilot study,  Catheter Cardiovasc Interv, 2013;81:335-9.
    Crossref | PubMed
  79. Ott C, Mahfoud F, Schmid A, et al., Renal denervation in moderate treatment resistant hypertension, J Am Coll Cardiol, 2013;62:1880-6.
    Crossref | PubMed
  80. Gazdar AF, Dammin GJ, Neural degeneration and regeneration in human renal transplants, N Engl J Med, 1970;283:222-4.
    Crossref | PubMed
  81. Blaufox MD, Lewis EJ, Jagger P, et al., Physiologic responses of the transplanted human kidney: sodium regulation and renin secretion, N Engl J Med, 1969;280:62-6.
    Crossref | PubMed
  82. Davies JE, Manisty CH, Petraco R, et al., First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study, Int J Cardiol, 2013;162:189-92.
    Crossref | PubMed
  83. Brandt MC, Mahfoud F, Reda S, et al., Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension, J Am Coll Cardiol, 2012;59:901-9.
    Crossref | PubMed
  84. Witkowski A, Prejbisz A, Florczak E, et al., Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea, Hypertension, 2011;58:559-65.
    Crossref | PubMed
  85. Mahfoud F, Schlaich M, Kindermann I, et al., Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study, Circulation, 2011;123:1940-46.
    Crossref | PubMed
  86. Ukena C, Bauer A, Mahfoud F, et al., Renal sympathetic denervation for treatment of electrical storm: first-in-man experience, Clin Res Cardiol, 2012;101:63-7.
    Crossref | PubMed
  87. Whitbourn R, Harding S, Rothman M, et al., Renal artery denervation with a new simultaneous multielectrode catheter for treatment of resistant hypertension: results from the Symplicity Spyral first-in-man study [abstract], J Am Coll Cardiol, 2013;62:B150.
    Crossref
  88. Ormiston JA, Watson T, van Pelt N, et al., Renal denervation for resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the Renal Hypertension Ablation System (RHAS) trial, EuroIntervention, 2013;9:70-4.
    Crossref | PubMed
  89. Ahmed H, Neuzil P, Skoda J, et al., Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of  drug-resistant hypertension, JACC Cardiovasc Interv, 2012;5:758-65.
    Crossref | PubMed
  90. Mazor M, Baird R, Stanley J, Evaluation of acute, sub-acute, and chronic renal artery nerve morphological changes following bipolar radiofrequency renal denervation treatment in the porcine model [abstract], J Am Coll Cardiol, 2013;62:B150.
    Crossref
  91. Honton B, Pathak A, Sauguet A, et al., First report of transradial renal denervation with the dedicated radiofrequency Iberis™ catheter, EuroIntervention, 2013; [Epub ahead of press].
    Crossref | PubMed
  92. Ladich E, Coleman L, Cabane V, et al., Arteria l media preservation associated with the paradise ultrasound renal denervation system: a next generation approach for treating resistant hypertension [abstract], J Am Coll Cardiol, 2013;62:B151-2.
    Crossref
  93. Mabin T, Sapoval M, Cabane V, et al., First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension, EuroIntervention, 2012;8:57-61.
    Crossref | PubMed
  94. Neuzil P, Petru J, Vondrakova D, et al., Circumferential therapeutic ultrasound for the treatment of resistant hypertension: preliminary results of human feasibility study (SOUND-ITV) [abstract], J Am Coll Cardiol, 2012;60:B101-2.
    Crossref
  95. Neuzil P, Whitbourn RJ, Starek Z, et al., Optimized external focused ultrasound for renal sympathetic denervation - wave ii trial [abstract], J Am Coll Cardiol, 2013;62:B20-B20.
    Crossref
  96. Owens CD, Gasper WJ, Rousselle S, et al., Peri-adventitial renal artery delivery of guanethidine monosulfate attenuates renal nerve function: preclinical experience and implication for resistant hypertension [abstract], J Am Coll Cardiol, 2011;58:B120.
    Crossref
  97. Fischell TA, Vega F, Raju N, et al., Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a  porcine model, EuroIntervention, 2013;9:140-7.
    Crossref | PubMed