PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of ehjLink to Publisher's site
 
Eur Heart J. 2017 April 14; 38(15): 1101–1111.
Published online 2016 July 12. doi:  10.1093/eurheartj/ehw303
PMCID: PMC5400047

Interventional procedures and future drug therapy for hypertension

Abstract

Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.

Keywords: Hypertension, Sympathetic nervous system, Renal denervation, Baroreflex activation, Arteriovenous anastomosis, Drug therapy

Introduction

Hypertension affects >1 billion people globally and is the number one risk factor for cardiovascular morbidity and mortality.1 Although many different classes of antihypertensive drug are available, side effects of drugs resulting in variable patient adherence are problematic.2,3 Additional drug therapies are therefore needed with excellent tolerability profiles in addition to proven safety and efficacy. Moreover, for those patients who either do not wish to take drugs lifelong or who experience disabling adverse effects from drug therapy, non-pharmacological measures over and above lifestyle modification are urgently required. We consider the newly emerging field of interventional procedures for hypertension and also what is on the horizon for novel pharmacological approaches to improve BP control.

Part I: interventional procedures for hypertension

An increasing number of technologies are in the pipeline at various stages of development (see Table 1), but this review will restrict itself to considering those therapies for which human feasibility studies have been published (see Figure 1). Regardless of which device therapy is being considered, it is important to recognize the need for the involvement of hypertension specialists in the optimal work up and management of patients to enable appropriate selection for therapy.48 Moreover, multidisciplinary collaboration among hypertension specialists, interventionalists, and physiologists will be essential for the design, execution, and analysis of forthcoming studies.

Table 1
Novel device technologies for treatment of hypertension
Figure 1
Interventional procedures for hypertension.

Renal sympathetic denervation

Rationale

Renal sympathetic nerves are important in the initiation of hypertension, and maintenance of the hypertensive state and interventions in animal models to abrogate renal sympathetic signalling prevent both the development of hypertension and lower BP.9,10 Increased renal sympathetic outflow, demonstrated in human hypertension, suggests that renal sympathetic nerves, conveniently located in a peri-arterial distribution, might be an attractive target for the treatment of hypertension.

Evidence to date

Selective endovascular renal sympathectomy has been available for the past 5 years using catheter-based renal ablation with radiofrequency (RF) energy. The Symplicity HTN-1 feasibility study ignited interest in the field after demonstrating substantial and safe office BP reduction of 27/17 mmHg in patients with resistant hypertension (RHTN) after 12 months of follow-up.11 The subsequent open label randomized non-sham-controlled Symplicity HTN-2 study also generated enormous publicity in the medical and lay press after demonstrating striking office BP reduction of 33/11 mmHg in RHTN patients treated with renal denervation (RDN) compared with control patients (P < 0.001).12 However, ambulatory BP monitoring, performed in only half the patients, showed less impressive reduction than office BP in the RDN group (11/7 mmHg).

Heterogeneity of response to RDN was beginning to emerge in these earliest studies and continued to be a feature of numerous small, uncontrolled studies of RDN thereafter.13 Criticisms of the accumulating RDN dataset iterated several common themes including sub-optimal work up for secondary hypertension, study bias due to lack of blinded BP endpoints, lack of sham-controlled procedure and inadequacy of follow-up.14 To address these and other valid issues, the Symplicity HTN-3 study was undertaken in the USA and published its report in early 2014 to the surprise of many clinicians and those in the medical device industry.15 This study, the largest of RDN to date, failed to demonstrate a difference in office and ambulatory BP lowering between patients treated with RDN and the sham (renal angiogram)-controlled group and thus failed its primary and secondary efficacy endpoints, although crucially the RDN procedure was deemed to be safe. Substantial limitations of this study have been subsequently identified by the investigators and have been the subject of extensive commentary.4,16,17 These include important differences in baseline medication usage between the groups, unstable medications at baseline and 40% medication changes in both groups throughout the study. Most worryingly, only 19 of 364 patients (5%) treated with RDN actually received bilateral ablation in all four quadrants of the renal artery. Not surprisingly, those that did receive per-protocol ablation therapy exhibited the greatest reductions in office, home, and ambulatory systolic BP (−24.3, −9.0, and −10.3 mmHg, respectively).17

Prior to Symplicity HTN-3 several thousand patients had been treated worldwide, mostly using the first-generation single-electrode Symplicity catheter. Most of these patients were treated as a standard of care rather than in clinical trials, although data for some was captured in the Global Symplicity Registry. The first report from this dataset indicates that RDN is a safe and effective treatment for RHTN: 6 months following RDN, the reductions in office and 24-h systolic BPs were 12 and 7 mmHg, respectively, for all 998 patients (baseline office BP 164 mmHg) and 20 and 9 mmHg for 323 patients with severe hypertension (baseline office BP 179 mmHg), respectively (P < 0.001 for all responses).18 Similarly, the UK Renal Denervation Affiliation has reported large reductions in office and ambulatory BP (22/9 and 12/7 mmHg, respectively, P < 0.001 for both) in 253 patients with severe hypertension (baseline office BP 185/102 mmHg) treated according to strict criteria with five different RDN catheters and suggests that real world application of RDN is successful when done per protocol.19

Despite the widespread adoption of RDN soon after the initial studies were published, there is a striking paucity of randomized controlled trial (RCT) data for RDN and the majority of the studies that exist are small in size with only 180 patients actively treated with RDN (excluding flawed Simplicity HTN-3), substantially less than the registries described earlier.12,15,2024 A recent meta-analysis of these studies indicates that among all 588 patients treated with RDN in RCTs, there were heterogeneous effects for office and ambulatory BP which were not significantly reduced compared with control (see Figure 2).25

Figure 2
Randomized controlled trials of renal denervation SBP, systolic BP; ABP, ambulatory BP. Image supplied courtesy of Dr K Chan.

Current technologies

Current approaches to RDN increasingly make use of multi-electrode catheters for RF ablation and irrigated balloon catheters for ultrasound (US) ablation.2629 A separate class of catheters makes us of microinjection of neurotoxin (e.g. alcohol) to chemically ablate renal nerves and has the potential advantage of facilitating deeper nerve injury whilst avoiding endothelial damage.30 Separately, a non-vascular catheter-based technology deploys a transurethral approach to ablate the renal pelvis which is richly innervated with afferent fibres and could be an alternative for patients with bleeding disorders or renal artery anatomy that is unsuitable for current endovascular ablation catheters.31 A wholly non-invasive US platform (Surround Sound™, Kona Medical) that targets the distal renal artery and bifurcation using advanced Doppler imaging is currently in clinical trials in Europe with a US pivotal study planned to start recruiting in 2016.

Concerns for the future

Is it acceptable to injure the renal artery to access a remote target?

Balloon catheterization of the renal artery and thermal energy arising during RF/US ablation result in acute vascular injury. Using optical coherence tomography, it was shown that diffuse vasospasm, oedema, and thrombus formation immediately follow single- and multi-electrode RDN with more thrombus noted with the latter.32 In addition, it was demonstrated that no-balloon and balloon catheters result in different patterns of thermal injury with dissection occurring more commonly with balloon treatment.33

The long-term consequences of renal artery injury following RDN are not established but it is worrying to see increasing reports of renal artery stenosis post-RDN which represents only the clinically manifest cases presenting with acute BP elevation.3436

How can the renal sympathetic nerves be precisely targeted?

Knowledge of human renal artery microanatomy was surprisingly limited until recently. However, a small human cadaveric study showed that these nerves lie in closest proximity to the lumen in the anterior and posterior quadrants of the distal renal artery, although at lesser density compared with proximally.37 In a porcine model, distal main renal artery plus branch ablation resulted in greater nerve destruction than proximal ablation alone and that increasing numbers of ablations are less critical than distal lesion placement.38,39

The importance of the renal artery microenvironment

The microenvironment of the renal artery is vastly different to the myocardium wherein much experience of ablation platforms resides: ventrally located heat sinks (e.g. veins) act to disperse thermal energy while dorsally located fibrous muscle sheaths can increase the extent of ablation.40,41 Blood pressure reduction post-RDN is exquisitely dependent upon the extent of nerve injury and ablation, which is largely dictated by the local tissue anatomy; irrigated multi-electrode catheters might therefore optimize ablation efficacy.40

Is nerve regrowth an issue or potential future concern?

Although re-innervation following RDN might occur, durable office BP reduction for up to 36 months was shown in the early Symplicity cohorts.42,43 Clinically, significant re-innervation has now been demonstrated in a pre-clinical sheep model: the occurrence of functional re-innervation in humans post-RDN has not been identified, although the transplanted human kidney seems not to demonstrate this.44,45

Are populations identifiable where renal sympathetic activity strikingly contributes (or not) to hypertension?

Beyond technical failure, the fact that renal nerves do not contribute to hypertension in all patients remains a potential clinical issue.46 Esler identified that with increasing age, renal norepinephrine spillover falls, suggesting that mechanisms other than sympathetic drive contribute to hypertension in the older adult.47 Ewen and colleagues reported diminishing RDN treatment effect in patients with isolated systolic hypertension, suggesting that patients with structural hypertension may not be ideal candidates for RDN therapy.48 Thus, ideal patient selection must identify if renal sympathetic nerves contribute to systemic hypertension before committing patients to the therapy.

Future directions

Experts are in joint agreement over the need for the field of RDN therapy to build a new clinical basis with additional RCTs, although there is debate over the requirement for sham control.5,6,49 Three strategies to further identify ideal patients, enhance technical success, and optimize patient and investigator blinding have evolved:

  1. Experimenting in drug naïve patients to eliminate the confounding effects of occult changes in pharmaceutical compliance on outcomes.
  2. Development of tools to identify patients with significant contribution of renal sympathetic nerves to hypertension, and which enable documentation of procedural and technical success.
  3. Requiring the use of ambulatory BP as an endpoint to eliminate the potential contribution of physician measurement bias on the outcome.

At this time, there is no obvious solution to nullify the impact of patient awareness of home BP on their pharmaceutical compliance and clinical behaviours.

Baroreflex activation therapy

Rationale

Arterial baroreceptors located along the carotid sinus and aortic arch are stimulated in response to arterial BP elevation and reflexively send afferent nerve impulses into the nucleus tractus solitarius in the central nervous system. This in turn leads to decreased sympathetic efferent output and BP lowering as well as increased parasympathetic outflow resulting in bradycardia.50,51

More than half a century ago studies in canines and in hypertensive humans demonstrated that electrical activation of the carotid baroreflex resulted in BP lowering.52,53 However, further development of the therapy was severely hampered by technological limitations and also surgical issues such as difficult implantation, unintended nerve, and muscle stimulation and nerve injuries.54,55

Procedure

Baroreflex activation therapy delivers electrical field stimulation at the carotid sinus to lower BP. The first-generation Rheos™ system utilized an implantable pulse generator and bipolar electrodes which were surgically attached to the carotid sinus under general anaesthesia. Subsequently, a second-generation device (Barostim Neo™) has replaced Rheos and encompasses a single unipolar electrode and miniaturized generator with improved battery life (see Figure 1).56 The procedure can now be done under conscious sedation with a much improved safety profile.

Clinical trial data

The Rheos device was initially evaluated in a feasibility study in 45 patients with RHTN which showed an average office BP reduction of 21/12 mmHg at 3 months and 33/22 mmHg at 2 years.57 Subsequently, in the Rheos Pivotal Trial,58 265 patients were randomized in a 2:1 fashion to early or delayed device activation (1 or 6 months post-implantation, respectively). There was no significant difference between groups in the primary efficacy end point of at least 10 mmHg drop in systolic BP. The study also failed to meet its early safety endpoint with 9% of patients developing transient (4.4%) or permanent (4.8%) facial nerve injury. Open label, non-randomized follow-up of the whole cohort reported that office systolic BP reduction of >30 mmHg was sustained up to 53 months with no important safety concerns.59 Subgroup analysis of the Rheos Pivotal Trial showed that most patients achieved target BP with unilateral therapy.60

A preliminary study with Barostim neo™ system in 30 patients with RHTN demonstrated office BP reduction of 26.0/12.4 mmHg at 6 months from a baseline of 171.7/99.5 mmHg. Importantly, there were shorter implantation and hospitalization times, as well as less immediate procedure-related complications compared with the first-generation system and no reports of either temporary or permanent facial nerve injury.61

Future directions

The Barostim Neo™ system has CE Mark approval for the treatment of RHTN and for heart failure. The manufacturer is currently undertaking the Barostim Hypertension Pivotal Trial (clinicaltrials.gov: NCT01679132) and a heart failure study (clinicaltrials.gov: NCT00718939). The therapy is costly (in excess of €20 000 for the hardware alone) and further efficacy/safety data for the Barostim Neo device will be required to better define the role of this therapy in both hypertension and heart failure.

Central iliac arteriovenous anastomosis

Rationale and mechanism of action

This novel approach is thought to principally address mechanical aspects of the circulation as opposed to primarily targeting the SNS. The central iliac arteriovenous (AV) anastomosis creates a fixed calibre conduit between the proximal arterial and low resistance venous circulation, which helps to restore the Windkessel function of the central circulation and thus providing a unique opportunity for improving proximal vascular compliance.6264 The anastomosis causes an immediate, significant reduction of BP, and systemic vascular resistance. The mechanism is related to the immediate reduction of effective arterial volume, vascular resistance, and buffering the contribution of reflected wave forms. Some sympathomodulatory effects are likely: by increasing venous oxygenation and right heart stretch through increased pre-load.62

Procedure

A 4-mm AV anastomosis between the external iliac artery and vein is created using a nitinol stent-like device (ROX AV coupler) in a 40-min catheterization laboratory procedure under fluoroscopic guidance (see Figure 3A).65 In contrast to an RDN procedure, AV coupler deployment is verifiable and reversible if required, resulting in the diversion of a calibrated amount of arterial blood (0.8–1 L/min) into the proximal large capacitance venous circuit (see Figure 3B). The immediate reduction in both systolic and diastolic BP obviates any contribution from placebo/Hawthorne effects.62,63

Figure 3
(A) ROX device and placement under fluoroscopic guidance. (B) Immediate, verifiable BP reduction with coupler opening and reversal with closure. (images reproduced with permission of ROX Medical).

Clinical data and safety considerations

Initially, the device was studied in patients with severe chronic obstructive pulmonary disease (COPD), with moderate improvement in 6 min walking distance and no safety signal.66 A subsequent open label study of 24 patients with COPD and mild hypertension demonstrated a significant reduction in office BP from 145/86 to 132/67 mmHg at 12 months leading to a repurposing of the device for the hypertension indication.67

In the ROX CONTROL HTN trial,68 83 patients with RHTN were randomized in a 1:1 ratio to receive standard care or insertion of AV coupler with standard care. At 6 months, office BP and ambulatory BP were reduced by 27/20 and 14/14 mmHg, respectively, in the coupler group (P < 0.0001 for all changes) while in the control group, there was no significant change in either. In a subgroup of patients who had prior RDN, there was highly significant office and ambulatory BP reduction (34/22 and 12/15 mmHg, respectively) in the coupler group at 6 months with no significant change in the control group for either. This suggests that AV coupler therapy may be of benefit in cases where sympathomodulation has failed.69

Ipsilateral venous stenosis was seen at ~6 months post-coupler insertion in 29% of the patients and this was managed by successfully by venoplasty and/or stenting in all patients. There was a significant reduction in hospitalizations for hypertensive urgencies in the coupler group.68

Future directions

Inevitably and mistakenly, the AV coupler is compared with upper limb fistulae for haemodialysis access. Important distinctions are that coupler flow is calibrated and that the anastomosis is not repeatedly punctured for dialysis access. Reassuringly, the anastomosis is fully reversible with a covered stent. To date, there are no reports of high output cardiac failure in treated patients and this has not been previously reported in fistulae of this diameter or in patients with shunt fractions this small.

The coupler is being further evaluated within a global registry study (clinicaltrials.gov: NCT1885390). A sham-controlled US-based IDE trial will begin enrolling in 2016. The immediate very significant reduction of BP and the ability of many patients to appreciate a thrill over the involved groin may reduce the success of sham in treated patients.

Carotid body ablation

Rationale and mechanism of action

Carotid bodies (CBs) are peripheral chemoreceptors that regulate respiratory minute ventilation and sympathetic tone in response to stimuli such as hypoxia, hypercapnia, hypoglycaemia, and acidosis.70,71 In both animal models and humans, increased CB tonicity can lead to hypertension and furthermore reversible inactivation of CB signalling can reduce systemic sympathetic tone in human hypertension and lower BP.70 In the 1940s, bilateral surgical resection of the CB in humans was commonly undertaken for asthma.72 The procedure was safe but did not lead to significant benefits in ventilatory parameters. However, in a subset of hypertensive patients, average systolic BP was lowered by 40 mmHg at 5 days post-operatively and this reduction was maintained out to 6 months.73

Clinical trial data and future perspectives

A proof of concept study in patients with RHTN who had unilateral CB ablation has demonstrated significant, durable office BP reduction of 23/12 mmHg at 6 months post-operatively in patients (8 of 15) with evidence of increased baseline CB activity. Hypoxic ventilatory drive was not disrupted and no serious adverse events were observed at up to 12 months of follow-up.74 Unilateral endovascular CB ablation for RHTN using the Cibiem Carotid Body Modulation System™ is currently being evaluated (clinicaltrials.gov: NCT02099851).

Part II: future drug therapy for hypertension

The challenges for new antihypertensive drug approaches are as follows:

  • to demonstrate meaningful BP reduction
  • to identify a population of hypertensive patients in whom a new drug could provide benefit
  • to modify hard outcomes in clinical trials meeting modern methodological standards.

This section will examine the main target of new antihypertensive drugs (see Table 2): the results of experimental and clinical trials will be reviewed emphasizing their potential advantages and disadvantages.

Table 2
Drugs in development for hypertension

Old systems revisited: the renin–angiotensin–aldosterone system

(Figure 4)

Figure 4
Drugs targeting the renin–angiotensin–aldosterone system. Neprilysin also contributes to breakdown of Angiotensin II and thus Neprilysin inhibition is combined with angiotensin receptor blockade in the ARNI class of drugs (angiotensin ...

Aldosterone receptor antagonism

Rationale

Aldosterone is a mineralocorticoid synthetized from 11-deoxycorticosterone, though the action of aldosterone synthase encoded by the CYP11B2 gene.75 This hormone binds to the mineralocorticoid receptor (MR) and leads to cardiac effects (myocardial hypertrophy and fibrosis) vascular changes (mediated by an increase in oxidative stress and decrease in nitric oxide bioavailability) and renal effects (sodium plus water retention).76

Clinical trial data

Currently, two novel pharmacological strategies target this pathway: aldosterone synthase inhibition and new non-steroidal MR antagonists (MRA). New MRA such as eplerenone do not have the anti-androgenic, partial oestrogen receptor agonist effects of spironolactone. However, eplerenone has a short half-life and is less potent than spironolactone and has never been formally established as an antihypertensive therapy.77

A newly available non-steroidal MRA (finerenone) has been described as more selective than spironolactone, and with greater affinity than eplerenone, for the MR.78 Despite these properties, finerenone, in common with many drugs targeting the renin–angiotensin–aldosterone system (RAAS), has been first tested in heart failure patients with reduced ejection fraction and CKD.79

Future directions

This pharmacological approach may be more appropriate for patients with comorbidities (e.g. hypertensive heart failure patients) rather than solely as an antihypertensive.

Inhibition of aldosterone synthesis

Rationale

Blockade of the MR causes reactive increase in RAAS components counteracting the expected benefits from MRA. This partly led to the development of aldosterone synthase inhibitors (ASIs) such as LCI699 which dose-dependently decreases plasma and urine aldosterone concentrations with concomitant increase in plasma renin activity.

Clinical trial data

Up to now, four Phase 2 studies have been performed in hypertensive patients, two showed that in comparison to placebo modest reductions in BP were recorded and when compared with eplerenone results were non-inferior, independent of the dose tested.8082 Two additional studies allowed identification of the maximal tolerated dose and safety plus efficacy of LCI699 in comparison to eplerenone as add on therapy in patients with resistant hypertension.83,84 The results were disappointing with inferior BP-lowering effect compared with eplerenone. The major drawback was lack of selectivity leading to off target effects related to CYP 11B1 inhibition and a significant increase in 11-deoxycorticosterone which can activate the MR and thus limit the beneficial effect of ASI.

Future directions

Currently, the development of ASI as an antihypertensive therapy is on hold. Recent identification of novel compounds namely pyridyl- or isoquinolinyl-substituted indolines and indoles, with greater selectivity for aldosterone synthase and prolonged half-life, has triggered new trials in the field of mineralocorticoid pathway-related cardio-renal disease.85 The recent conclusion from the PATHWAY 2 trial that Spironolactone was the most effective add-on drug for the treatment of resistant hypertension reinforces the importance of the aldosterone pathway in the pathophysiology of hypertension and extra-renal conditions.86

Angiotensin I and II receptors as targets

Rationale

Stimulation of the angiotensin type 2 (AT2) receptor leads to opposite effects from angiotensin type 1 (AT1) receptor stimulation through binding of ligands such as Angiotensin (Ang) II, III, IV, and Ang-(1–7) (see Figure 1). Ang-(1–7) produced by angiotensin-converting enzyme 2 (ACE2) from Ang II opposes AT1 receptor-mediated effects via its binding to the Mas receptor, though it also binds to AT2 and even partially to AT1 receptors.87

Clinical trial data

Four candidate drugs have been specifically developed to target this pathway, three peptidic agonists and one non-peptidic agonist. Despite the data on AT2 receptor-mediated vasodilation, some of these drugs do not have any effects on BP; some like C21 have pleiotropic effects explaining the observed anti-fibrotic and anti-inflammatory effects.88,89

Ang (1–7) has multiple cardioprotective effects but weak vasodilatatory properties making it less suitable as an antihypertensive agent.90 Similarly, ACE2 stimulation lowers BP but more because of its ability to reduce Ang II concentration than alter production of Ang-(1–7).91

Future directions

The lack of BP-lowering effect despite AT2-mediated vasodilation suggests that these therapies will not be developed for hypertensive patients. However, despite weak haemodynamic effects, the ACE2—Ang-(1–7)—Mas receptor axis is potentially a more promising target. The short half-life of Ang-(1–7) and its agonist effect on AT1 receptors at high concentration led to the development of peptidic and non-peptidic drugs, lowering BP in hypertensive animals using the encapsulated form.92 Clinical trials are needed to assess the benefit–risk ratio of this approach.

Angiotensin as a target

Rationale

At the brain level, the metalloproteinases aminopeptidase A (APA) and aminopeptidase N are, respectively, involved in the metabolism of Ang II and Ang III (a peripheral AT2 agonist but acting centrally as an AT1 ligand) and also Ang IV (see Figure 4).93,94 Ang III binds receptors with affinity for Ang II leading to an increase in BP via direct and indirect activation of the central sympathetic nervous system (through baroreflex inhibition) and also through activation of the arginine–vasopressin pathway.95

Experimental trial data

Inhibition of APA by EC33 has been logically identified as a potential target for the management of hypertension.96 Recently, the orally administered pro-drug RB150, which after crossing the blood–brain barrier is converted to EC33, normalizes BP for several hours through the aforementioned mechanisms of action without affecting systemic RAAS activity suggesting a potential role for the combination of APA inhibitors with peripheral RAAS blockers.

Future directions

The above observations led to a first in man trial confirming the safety of a dose-escalating approach in healthy volunteers paving the way for further exploratory studies in the treatment of hypertension.97 This central inhibition of the RAAS could provide some particular added value in difficult to control hypertensive patients and possibly those with neurovascular diagnoses.

The renin–angiotensin–aldosterone system and vaccines

Rationale

The development of vaccines targeting the RAAS for the treatment of hypertension is a long running story comprising three major epochs underpinned by the aims to target patients with compliance issues and also to expand hypertension therapy through involvement of a new immunomodulatory pathway.

Clinical trial data

Initial therapies targeting renin, angiotensin, and ACE were associated with autoimmune diseases and subsequent refinement led to a more controlled immunogenic response albeit with conflicting results in term of BP reduction.98,99 The second phase of development was based on development of a novel immunization agent associated with a significant reduction of BP, predictable adverse events (as seen in other vaccine trials) and with pharmacokinetic data compatible with the need for several injections per year.100 In the most recent phase, trials have investigated not only new doses and different timing of immunization (utilizing the concept of accelerated immunization) but also novel targets (angiotensin receptors, Ang II) and vectors (virus) identifying that antibody titres, affinities, and type of hypertension (baseline level of BP, severity of the disease) have to be take into account to better inform the development of future vaccine therapy.100102

Future directions

There remain concerns regarding pharmacokinetics and risk management of a vaccine-based approach inhibiting physiological responses to medical emergencies.

New systems explored

Neprilysin inhibition

Rationale

An increase in natriuretic peptides (NPs; atrial/brain/C-type) and urodilatin concentration arises from inhibition of neprilysin, which degrades these peptides and in addition numerous vasoconstrictor peptides.103 This dual action explains the need for neprilysin inhibitor to be combined with blockade of the RAAS or endothelin-converting enzyme inhibitors (see Figure 4).

Clinical trial data

LCZ696 was the first in class angiotensin receptor-neprilysin inhibitor (ARNI) associated with a decrease in BP greater than the BP-lowering effect of valsartan or sacubutril alone.104 LCZ696 was also shown to safely reduce BP in severely hypertensive Asian patients (office BP > 180/110 mmHg) and was well tolerated.105 Modest effects on BP led to re-purposing of the drug to the field of heart failure both with and without reduced ejection fraction.

Future directions

Hypertensive patients with reduced ejection fraction-related heart failure could be the patient of choice for LCZ 696 (now Entresto®).106

Natriuretic peptide receptor agonism

Rationale

Natriuretic peptide receptor (NPR) agonists (which can reduce BP and lead to cardio and nephroprotective effects) are also being developed as an alternative to NP degradation (Figure 4).107

Clinical trial data

A subcutaneous dose of an NPR agonist was associated with a significant BP reduction compared with placebo in hypertensive patients (ClincialTrials.gov: NCT00686803). Angiotensin-converting enzyme inhibitors act synergistically and suggest that this approach could be used as an adjunct to therapy for patient with uncontrolled hypertension.

Future directions

Clinical trials with nesiritide, a recombinant form of human B-type NP, infused in patients with advanced heart failure, led to disappointing results including worsening of renal function or heart failure. These mixed results justify further investigation into the utility of targeting the NP system in the setting of hypertension.108,109

Vasoactive intestinal peptide as a target

Rationale

Vasoactive intestinal peptide (VIP) is a neuropeptide with vasodilatatory, inotropic, and chronotropic properties.110,111

Clinical trial data

This peptide binds to both VPAC1 and VPAC2 receptors, leading, respectively, to gastrointestinal side effects (as seen in patients with VIPoma) and beneficial haemodynamic effects.112 To enhance the very short half-life of VIP, a peptide has been developed (Vasomera); it was found to be safe and well tolerated following a single injection in a study including patients with primary hypertension (ClinicalTrials.gov: NCT01523067, NCT01873885).

Future directions

The parenteral approach suggests that this drug could be used in the emergency setting.

Sodium transport as a target

Rationale

Intestinal sodium intake has been involved in the pathogenesis of hypertension and mainly related to the activity of electroneutral sodium/hydrogen exchangers located in enterocytes.113

Clinical trial data

Inhibition of sodium/hydrogen exchangers by orally administered tenapanor increases intestinal sodium excretion and lowers BP in an experimental model of HTN.114,115 Similarly, an inhibitor of sodium-glucose co-transporter type 2, empagliflozin, has been investigated in a large outcome RCT and was associated with a reduction of the primary composite cardiovascular endpoint. In this case, increased urinary sodium and glucose excretion partly explained the decrease in BP in diabetic patients and suggests a promising new avenue in the field of sodium modulation for human hypertension.116

Future directions

Recent data suggest that this approach could be of interest for hypertensive diabetic patients and perhaps also be beneficial in patients with hypertension and heart failure.

Inhibition of noradrenaline synthesis

Rationale

Dopamine β-hydroxylase (DBH) is involved in the production of noradrenaline from dopamine in pre-ganglionic neurons.

Clinical trial data

Etamicastat is a reversible peripheral inhibitor of DBH which has been studied in mild-to-moderate hypertensive patients and led to a significant dose-dependent reduction in 24 ambulatory BP without any safety signal.117

Future directions

This new centrally acting drug could be used in difficult to control hypertensive patient or in hypertensives with dysautonomia.

Future tools and targets for drug development

Genetic and molecular aspect of hypertension

Research in this field has moved on from studies of monogenic forms of hypertension to genome-wide association studies which have confirmed the role of common genetic variants in hypertension and are also helping to decipher novel pathways of BP regulation which could lead to drug optimization or new drug development.118 A newly discovered pathway modulated by the uromodulin gene shows promise in yielding future drug targets.119 Evidence from genetic studies also suggests that mechanisms involved in the regulation of NPs could be considered as a potential target or marker of response. Hence, activators of NPs, such as corin, NP target receptors, or enzymes involved in the degradation of NP exhibit a level of expression or activity influenced by genetic variation.120,121 Identification of these variants could explain response to drugs and potentially inform the future prognosis of patients and also identify new treatment targets for hypertension.

Immunity and inflammation

It has been recognized that immunity contributes to human hypertension.122,123 Numerous stimuli involved in the pathogenesis of hypertension (e.g. angiotensin II, salt, and catecholamines) are also recognized to impact upon T lymphocytes (both number and type such as T regulatory/helper) and derived cytokines production (IL-17, IFN-γ, TNF-α, or IL-6) leading to both sustained BP elevation (through enhanced sodium retention, SNS activation, or increased vascular resistance) and end organ damage. Antihypertensive therapies are known to influence these factors such as MRA (spironolactone).122 Moreover, hypertension, by increasing oxidative stress, also contributes to immune activation in hypertension through mechanisms involving dendritic cells.123 However, in trials investigating drugs known to affect these pathways or cells (e.g. in the field of psoriasis), immunomodulation had no effect on BP. These observations potentially suggest a more active role of B lymphocytes and the need to further pursue our understanding of the interaction between immunity and BP. Abatacept, a fusion protein known to inhibit T-cell activation and used in various inflammatory condition, is currently being investigated as an adjunctive therapy in resistant hypertension (ClinicalTrials.gov: NCT02232880).

Dietary management of hypertension

A diet emphasizing flavonoid-rich fruits and vegetables achieves a BP reduction of approximately half that observed with the DASH diet.124,125 The major pharmacodynamic effect was restoration of endothelial function, either directly, by affecting nitric oxide levels, or indirectly, through other pathways (i.e. antioxidant, anti-inflammatory, or acetylcholine -related). Quercetin has demonstrated the most consistent BP-lowering effect in animal and human studies, irrespective of dose, duration, or disease status.126 However, further research on the safety and efficacy of the flavonoids is required before any of them can be used by humans, presumably in supplement form, at the doses required for therapeutic benefit.

Authors’ contributions

M. L. handled funding and supervision. M.L., P.S., A.P. acquired the data. M.L., P.S., A.P. conceived and designed the research. M.L., P.S., A.P. drafted the manuscript. M.L., P.S., A.P. made critical revision of the manuscript for key intellectual content.

Conflict of interest: M.D.L. has received honoraria from Medtronic Inc., St Jude Medical, ROX Medical and Cardiosonic. P.A.S. is an employee of Rox Medical, Inc. He has stock options in Rox Medical, Inc., Cibiem Inc. A.P. has received speaker fees, consulting fees, or research grants or has been sponsored for medical meeting by: Ablative Solutions, Abbott, Astra Zeneca, BMS, CVRx, Daichii, Medtronic Inc., MSD, Novartis, Recor Medical, Servier, and St Jude Medical.

Funding

Funding to pay the Open Access publication charges for this article was provided by William Harvey Research Institute, Barts NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.

References

1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–223. [PubMed]
2. Bardage C, Isacson DG Self-reported side-effects of antihypertensive drugs: an epidemiological study on prevalence and impact on health-state utility. Blood Press 2000;9:328–334. [PubMed]
3. Elliott WJ. Improving outcomes in hypertensive patients: focus on adherence and persistence with antihypertensive therapy. J Clin Hypertens 2009;11:376–382. [PubMed]
4. Lobo MD, de Belder MA, Cleveland T, Collier D, Dasgupta I, Deanfield J, Kapil V, Knight C, Matson M, Moss J, Paton JF, Poulter N, Simpson I, Williams B, Caulfield MJ, British Hypertension Society, British Cardiovascular Society, British Cardiovascular Intervention Society, Renal Association.. Joint UK societies’ 2014 consensus statement on renal denervation for resistant hypertension. Heart 2015;101:10–16. [PMC free article] [PubMed]
5. Mahfoud F, Luscher TF, Andersson B, Baumgartner I, Cifkova R, Dimario C, Doevendans P, Fagard R, Fajadet J, Komajda M, Lefevre T, Lotan C, Sievert H, Volpe M, Widimsky P, Wijns W, Williams B, Windecker S, Witkowski A, Zeller T, Bohm M, European Society of Cardiology. Expert consensus document from the European Society of Cardiology on catheter-based renal denervation. Eur Heart J 2013;34:2149–2157. [PubMed]
6. White WB, Galis ZS, Henegar J, Kandzari DE, Victor R, Sica D, Townsend RR, Turner JR, Virmani R, Mauri L Renal denervation therapy for hypertension: pathways for moving development forward. J Am Soc Hypertens 2015;9:341–350. [PubMed]
7. Zannad F, Stough WG, Mahfoud F, Bakris GL, Kjeldsen SE, Kieval RS, Haller H, Yared N, De Ferrari GM, Pina IL, Stein K, Azizi M Design considerations for clinical trials of autonomic modulation therapies targeting hypertension and heart failure. Hypertension 2015;65:5–15. [PubMed]
8. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Ryden L, Sirenko Y, Stanton A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA 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. [PubMed]
9. DiBona GF, Esler M Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010;298:R245–R253. [PubMed]
10. DiBona GF, Kopp UC Neural control of renal function. Physiol Rev 1997;77:75–197. [PubMed]
11. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–1281. [PubMed]
12. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M, Mahfoud F, Sievert H, Wunderlich N, Rump LC, Vonend O, Uder M, Lobo M, Caulfield M, Erglis A, Azizi M, Sapoval M, Thambar S, Persu A, Renkin J, Schunkert H, Weil J, Hoppe UC, Walton T, Scheinert D, Binder T, Januszewicz A, Witkowski A, Ruilope LM, Whitbourn R, Bruck H, Downes M, Lüscher TF, Jardine AG, Webster MW, Zeller T, Sadowski J, Bartus K, Straley CA, Barman NC, Lee DP, Witteles RM, Bhalla V, Massaro JM Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet 2010;376:1903–1909. [PubMed]
13. Persu A, Jin Y, Azizi M, Baelen M, Volz S, Elvan A, Severino F, Rosa J, Adiyaman A, Fadl Elmula FE, Taylor A, Pechere-Bertschi A, Wuerzner G, Jokhaji F, Kahan T, Renkin J, Monge M, Widimsky P, Jacobs L, Burnier M, Mark PB, Kjeldsen SE, Andersson B, Sapoval M, Staessen JA, European Network CroRD. Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hyperten 2014;28:150–156. [PMC free article] [PubMed]
14. Persu A, Renkin J, Thijs L, Staessen JA Renal denervation: ultima ratio or standard in treatment-resistant hypertension. Hypertension 2012;60:596–606. [PMC free article] [PubMed]
15. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL, SYMPLICITY HTN-3. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–1401. [PubMed]
16. Esler M. Renal denervation for hypertension: observations and predictions of a founder. Eur Heart J 2014;35:1178–1185. [PubMed]
17. Kandzari DE, Bhatt DL, Brar S, Devireddy CM, Esler M, Fahy M, Flack JM, Katzen BT, Lea J, Lee DP, Leon MB, Ma A, Massaro J, Mauri L, Oparil S, O'Neill WW, Patel MR, Rocha-Singh K, Sobotka PA, Svetkey L, Townsend RR, Bakris GL Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J 2015;36:219–227. [PMC free article] [PubMed]
18. Bohm M, Mahfoud F, Ukena C, Hoppe UC, Narkiewicz K, Negoita M, Ruilope L, Schlaich MP, Schmieder RE, Whitbourn R, Williams B, Zeymer U, Zirlik A, Mancia G, on behalf of the GSR Investigators. First report of the global SYMPLICITY registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension 2015;65:766–774. [PubMed]
19. Sharp AS, Davies JE, Lobo MD, Bent CL, Mark PB, Burchell AE, Thackray SD, Martin U, McKane WS, Gerber RT, Wilkinson JR, Antonios TF, Doulton TW, Patterson T, Clifford PC, Lindsay A, Houston GJ, Freedman J, Das N, Belli AM, Faris M, Cleveland TJ, Nightingale AK, Hameed A, Mahadevan K, Finegold JA, Mather AN, Levy T, D'Souza R, Riley P, Moss JG, Di Mario C, Redwood SR, Baumbach A, Caulfield MJ, Dasgupta I Renal artery sympathetic denervation: observations from the UK experience. Clin Res Cardiol 2016;105:544–552. [PMC free article] [PubMed]
20. Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, Midulla M, Mounier-Vehier C, Courand PY, Lantelme P, Denolle T, Dourmap-Collas C, Trillaud H, Pereira H, Plouin PF, Chatellier G, Renal Denervation for Hypertension (DENERHTN) Investigators. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015;385:1957–1965. [PubMed]
21. Desch S, Okon T, Heinemann D, Kulle K, Rohnert K, Sonnabend M, Petzold M, Muller U, Schuler G, Eitel I, Thiele H, Lurz P Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension 2015;65:1202–1208. [PubMed]
22. Fadl Elmula FE, Hoffmann P, Larstorp AC, Fossum E, Brekke M, Kjeldsen SE, Gjonnaess E, Hjornholm U, Kjaer VN, Rostrup M, Os I, Stenehjem A, Hoieggen A Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension 2014;63:991–999. [PubMed]
23. Kario K, Ogawa H, Okumura K, Okura T, Saito S, Ueno T, Haskin R, Negoita M, Shimada K, SYMPLICITY HTN-Japan Investigators. SYMPLICITY HTN-Japan – first randomized controlled trial of catheter-based renal denervation in Asian patients. Circ J 2015;79:1222–1229. [PubMed]
24. Rosa J, Widimsky P, Tousek P, Petrak O, Curila K, Waldauf P, Bednar F, Zelinka T, Holaj R, Strauch B, Somloova Z, Taborsky M, Vaclavik J, Kocianova E, Branny M, Nykl I, Jiravsky O, Widimsky J Jr Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study. Hypertension 2015;65:407–413. [PubMed]
25. Fadl Elmula FE, Jin Y, Yang WY, Thijs L, Lu YC, Larstorp AC, Persu A, Sapoval M, Rosa J, Widimsky P, Jacobs L, Renkin J, Petrak O, Chatellier G, Shimada K, Widimsky J, Kario K, Azizi M, Kjeldsen SE, Staessen JA, European Network Coordinating Research On Renal Denervation (ENCOReD) Consortium. Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension. Blood Press 2015;24:263–274. [PubMed]
26. Kapil V, Jain AK, Lobo MD Renal sympathetic denervation – a review of applications in current practice. Interv Cardiol Rev 2014;9:54–61.
27. Kiuchi MG, Maia GL, de Queiroz Carreira MA, Kiuchi T, Chen S, Andrea BR, Graciano ML, Lugon JR Effects of renal denervation with a standard irrigated cardiac ablation catheter on blood pressure and renal function in patients with chronic kidney disease and resistant hypertension. Eur Heart J 2013;34:2114–2121. [PubMed]
28. Worthley SG, Tsioufis CP, Worthley MI, Sinhal A, Chew DP, Meredith IT, Malaiapan Y, Papademetriou V Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 2013;34:2132–2140. [PMC free article] [PubMed]
29. Pathak A, Coleman L, Roth A, Stanley J, Bailey L, Markham P, Ewen S, Morel C, Despas F, Honton B, Senard JM, Fajadet J, Mahfoud F Renal sympathetic nerve denervation using intraluminal ultrasound within a cooling balloon preserves the arterial wall and reduces sympathetic nerve activity. EuroIntervention 2015;11:477–484. [PubMed]
30. Fischell TA, Vega F, Raju N, Johnson ET, Kent DJ, Ragland RR, Fischell DR, Almany SL, Ghazarossian VE Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model. EuroIntervention 2013;9:140–147. [PubMed]
31. Heuser RR, Mhatre AU, Buelna TJ, Berci WL, Hubbard BS A novel non-vascular system to treat resistant hypertension. EuroIntervention 2013;9:135–139. [PubMed]
32. Templin C, Jaguszewski M, Ghadri JR, Sudano I, Gaehwiler R, Hellermann JP, Schoenenberger-Berzins R, Landmesser U, Erne P, Noll G, Luscher TF Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the Simplicity catheter system and the EnligHTN multi-electrode renal denervation catheter. Eur Heart J 2013;34:2141–2148, 8b. [PMC free article] [PubMed]
33. Karanasos A, Van Mieghem N, Bergmann MW, Hartman E, Ligthart J, van der Heide E, Heeger CH, Ouhlous M, Zijlstra F, Regar E, Daemen J Multimodality intra-arterial imaging assessment of the vascular trauma induced by balloon-based and nonballoon-based renal denervation systems. Circ Cardiovasc Interv 2015;8:e002474. [PubMed]
34. Diego-Nieto A, Cruz-Gonzalez I, Martin-Moreiras J, Rama-Merchan JC, Rodriguez-Collado J, Sanchez-Fernandez PL Severe renal artery stenosis after renal sympathetic denervation. JACC Cardiovasc Interv 2015;8:e193–e194. [PubMed]
35. Persu A, Sapoval M, Azizi M, Monge M, Danse E, Hammer F, Renkin J Renal artery stenosis following renal denervation: a matter of concern. J Hypertens 2014;32:2101–2105. [PubMed]
36. Vonend O, Antoch G, Rump LC, Blondin D Secondary rise in blood pressure after renal denervation. Lancet 2012;380:778. [PubMed]
37. Sakakura K, Ladich E, Cheng Q, Otsuka F, Yahagi K, Fowler DR, Kolodgie FD, Virmani R, Joner M Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64:635–643. [PubMed]
38. Mahfoud F, Tunev S, Ewen S, Cremers B, Ruwart J, Schulz-Jander D, Linz D, Davies J, Kandzari DE, Whitbourn R, Bohm M, Melder RJ Impact of lesion placement on efficacy and safety of catheter-based radiofrequency renal denervation. J Am Coll Cardiol 2015;66:1766–1775. [PubMed]
39. Tzafriri AR, Mahfoud F, Keating JH, Markham PM, Spognardi A, Wong G, Fuimaono K, Bohm M, Edelman ER Innervation patterns may limit response to endovascular renal denervation. J Am Coll Cardiol 2014;64:1079–1087. [PMC free article] [PubMed]
40. Tzafriri AR, Keating JH, Markham PM, Spognardi AM, Stanley JR, Wong G, Zani BG, Highsmith D, O'Fallon P, Fuimaono K, Mahfoud F, Edelman ER Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. Sci Transl Med 2015;7:285ra65. [PMC free article] [PubMed]
41. Esler M. Renal denervation: not as easy as it looks. Sci Transl Med 2015;7:285fs18. [PubMed]
42. Esler MD, Bohm M, Sievert H, Rump CL, Schmieder RE, Krum H, Mahfoud F, Schlaich MP Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial. Eur Heart J 2014;35:1752–1759. [PubMed]
43. Krum H, Schlaich MP, Sobotka PA, Bohm M, Mahfoud F, Rocha-Singh K, Katholi R, Esler MD Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:622–629. [PubMed]
44. Booth LC, Nishi EE, Yao ST, Ramchandra R, Lambert GW, Schlaich MP, May CN Reinnervation of renal afferent and efferent nerves at 5.5 and 11 months after catheter-based radiofrequency renal denervation in sheep. Hypertension 2015;65:393–400. [PubMed]
45. Hansen JM, Abildgaard U, Fogh-Andersen N, Kanstrup IL, Bratholm P, Plum I, Strandgaard S The transplanted human kidney does not achieve functional reinnervation. Clin Sci (Lond) 1994;87:13–20. [PubMed]
46. Iliescu R, Lohmeier TE, Tudorancea I, Laffin L, Bakris GL Renal denervation for the treatment of resistant hypertension: review and clinical perspective. Am J Physiol Renal Physiol 2015;309:F583–F594. [PubMed]
47. Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking G, Anderson W, Lambert G Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 1988;11:3–20. [PubMed]
48. Ewen S, Ukena C, Linz D, Kindermann I, Cremers B, Laufs U, Wagenpfeil S, Schmieder RE, Bohm M, Mahfoud F Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension. Hypertension 2015;65:193–199. [PubMed]
49. Weber MA, Kirtane A, Mauri L, Townsend RR, Kandzari DE, Leon MB Renal denervation for the treatment of hypertension: making a new start, getting it right. J Clin Hypertens 2015;17:743–750. [PubMed]
50. Victor RG. Carotid baroreflex activation therapy for resistant hypertension. Nat Rev Cardiol 2015;12:451–463. [PubMed]
51. Mancia G, Grassi G The autonomic nervous system and hypertension. Circ Res 2014;114:1804–1814. [PubMed]
52. Bilgutay AM, Lillehei CW Treatment of hypertension with an implantable electronic device. JAMA 1965;191:649–653. [PubMed]
53. Carlsten A, Folkow B, Grimby G, Hamberger CA, Thulesius O Cardiovascular effects of direct stimulation of the carotid sinus nerve in man. Acta Physiol Scand 1958;44:138–145. [PubMed]
54. Grossman W. Complications of carotid-sinus stimulation. N Engl J Med 1969;281:103. [PubMed]
55. Scheffers IJ, Kroon AA, de Leeuw PW Carotid baroreflex activation: past, present, and future. Curr Hypertens Rep 2010;12:61–66. [PMC free article] [PubMed]
56. Alnima T, de Leeuw PW, Kroon AA Baropacing as a new option for treatment of resistant hypertension. Eur J Pharmacol 2015;763(Pt A):23–27. [PubMed]
57. Scheffers IJ, Kroon AA, Schmidli J, Jordan J, Tordoir JJ, Mohaupt MG, Luft FC, Haller H, Menne J, Engeli S, Ceral J, Eckert S, Erglis A, Narkiewicz K, Philipp T, de Leeuw PW Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–1258. [PubMed]
58. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, de Leeuw PW, Sica DA Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011;58:765–773. [PubMed]
59. Bakris GL, Nadim MK, Haller H, Lovett EG, Schafer JE, Bisognano JD 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;6:152–158. [PubMed]
60. de Leeuw PW, Alnima T, Lovett E, Sica D, Bisognano J, Haller H, Kroon AA Bilateral or unilateral stimulation for baroreflex activation therapy. Hypertension 2015;65:187–192. [PubMed]
61. Hoppe UC, Brandt MC, Wachter R, Beige J, Rump LC, Kroon AA, Cates AW, Lovett EG, Haller H 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;6:270–276. [PubMed]
62. Burchell AE, Lobo MD, Sulke N, Sobotka PA, Paton JF Arteriovenous anastomosis: is this the way to control hypertension? Hypertension 2014;64:6–12. [PubMed]
63. Kapil V, Sobotka PA, Saxena M, Mathur A, Knight C, Dolan E, Stanton A, Lobo MD Central iliac arteriovenous anastomosis for hypertension: targeting mechanical aspects of the circulation. Curr Hypertens Rep 2015;17:585. [PMC free article] [PubMed]
64. Westerhof N, Lankhaar JW, Westerhof BE The arterial Windkessel. Med Biol Eng Comput 2009;47:131–141. [PubMed]
65. Foran JP, Jain AK, Casserly IP, Kandzari DE, Rocha-Singh KJ, Witkowski A, Katzen BT, Deaton D, Balmforth P, Sobotka PA The ROX coupler: creation of a fixed iliac arteriovenous anastomosis for the treatment of uncontrolled systemic arterial hypertension, exploiting the physical properties of the arterial vasculature. Catheter Cardiovasc Interv 2015;85:880–886. [PubMed]
66. Faul JL, Galindo J, Posadas-Valay R, Elizondo-Riojas G, Martinez A, Cooper CB An arteriovenous fistula increases exercise capacity in patients with COPD. Chest 2010;138:52–58. [PubMed]
67. Faul J, Schoors D, Brouwers S, Scott B, Jerrentrup A, Galvin J, Luitjens S, Dolan E Creation of an iliac arteriovenous shunt lowers blood pressure in chronic obstructive pulmonary disease patients with hypertension. J Vasc Surg 2014;59:1078–1083. [PubMed]
68. Lobo MD, Sobotka PA, Stanton A, Cockcroft JR, Sulke N, Dolan E, van der Giet M, Hoyer J, Furniss SS, Foran JP, Witkowski A, Januszewicz A, Schoors D, Tsioufis K, Rensing BJ, Scott B, Ng GA, Ott C, Schmieder RE, Investigators RCH. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet 2015;385:1634–1641. [PubMed]
69. Brier TJ, Jain AK, Lobo MD Central arteriovenous anastomosis for hypertension: it is not all about sympathomodulation. Future Cardiol 2015;11:503–506. [PubMed]
70. Paton JF, Sobotka PA, Fudim M, Engelman ZJ, Hart EC, McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell A, Ratcliffe L, Nightingale A The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension 2013;61:5–13. [PubMed]
71. Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev 1994;74:543–594. [PubMed]
72. Nakayama K. Surgical removal of the carotid body for bronchial asthma. Dis Chest 1961;40:595–604. [PubMed]
73. Winter B, Whipp BJ Immediate effects of bilateral carotid body resection on total respiratory resistance and compliance in humans. Adv Exp Med Biol 2004;551:15–21. [PubMed]
74. Ratcliffe L, Hart EC, Patel N, Szydler A, Chrostowska M, Wolf J, Engelman Z, Lobo MD, Nightingale A, Narkiewicz K, Paton JFR Unilateral carotid body resection as an anti-hypertensive strategy: a proof of principle study in resistant hypertensive patients. J Hum Hypertens 2015;29:625.
75. Kawamoto T, Mitsuuchi Y, Toda K, Yokoyama Y, Miyahara K, Miura S, Ohnishi T, Ichikawa Y, Nakao K, Imura H Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proc Natl Acad Sci USA 1992;89:1458–1462. [PubMed]
76. Ruilope LM. Aldosterone, hypertension, and cardiovascular disease: an endless story. Hypertension 2008;52:207–208. [PubMed]
77. Colussi G, Catena C, Sechi LA Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary hypertension. J Hypertens 2013;31:3–15. [PubMed]
78. Liu LC, Schutte E, Gansevoort RT, van der Meer P, Voors AA Finerenone : third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease. Expert Opin Investig Drugs 2015;24:1123–1135. [PubMed]
79. Bramlage P, Swift SL, Thoenes M, Minguet J, Ferrero C, Schmieder RE Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail 2016;18:28–37. [PubMed]
80. Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin PF Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 2010;56:831–838. [PubMed]
81. Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, Lefkowitz MP, Menard J Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 2011;124:1945–1955. [PubMed]
82. Schumacher CD, Steele RE, Brunner HR Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy. J Hypertens 2013;31:2085–2093. [PMC free article] [PubMed]
83. Andersen K, Hartman D, Peppard T, Hermann D, Van Ess P, Lefkowitz M, Trapani A The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study. J Clin Hypertens 2012;14:580–587. [PubMed]
84. Karns AD, Bral JM, Hartman D, Peppard T, Schumacher C Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens 2013;15:186–192. [PubMed]
85. Yin L, Hu Q, Emmerich J, Lo MM, Metzger E, Ali A, Hartmann RW Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors. J Med Chem 2014;57:5179–5189. [PubMed]
86. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ, British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015;386:2059–2068. [PMC free article] [PubMed]
87. Bosnyak S, Widdop RE, Denton KM, Jones ES Differential mechanisms of ang (1–7)-mediated vasodepressor effect in adult and aged candesartan-treated rats. Int J Hypertens 2012;2012:192567. [PMC free article] [PubMed]
88. Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci (Lond) 2011;121:297–303. [PubMed]
89. Kljajic ST, Widdop RE, Vinh A, Welungoda I, Bosnyak S, Jones ES, Gaspari TA Direct AT(2) receptor stimulation is athero-protective and stabilizes plaque in apolipoprotein E-deficient mice. Int J Cardiol 2013;169:281–287. [PubMed]
90. Iusuf D, Henning RH, van Gilst WH, Roks AJ Angiotensin-(1–7): pharmacological properties and pharmacotherapeutic perspectives. Eur J Pharmacol 2008;585:303–312. [PubMed]
91. Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, Haystead TA, Donoghue M, Breitbart RE, Acton SL, Rockman HA, Coffman TM Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 2006;116:2218–2225. [PubMed]
92. Ferreira AJ, Santos RA, Bradford CN, Mecca AP, Sumners C, Katovich MJ, Raizada MK Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension 2010;55:207–213. [PMC free article] [PubMed]
93. Danziger RS. Aminopeptidase N in arterial hypertension. Heart Fail Rev 2008;13:293–298. [PubMed]
94. Reaux A, Iturrioz X, Vazeux G, Fournie-Zaluski MC, David C, Roques BP, Corvol P, Llorens-Cortes C Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. Biochem Soc Trans 2000;28:435–440. [PubMed]
95. Yugandhar VG, Clark MA Angiotensin III: a physiological relevant peptide of the renin angiotensin system. Peptides 2013;46:26–32. [PubMed]
96. Marc Y, Gao J, Balavoine F, Michaud A, Roques BP, Llorens-Cortes C Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. Hypertension 2012;60:411–418. [PubMed]
97. Balavoine F, Azizi M, Bergerot D, De Mota N, Patouret R, Roques BP, Llorens-Cortes C Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug. Clin Pharmacokinet 2014;53:385–395. [PubMed]
98. Michel JB, Guettier C, Reade R, Sayah S, Corvol P, Menard J Immunologic approaches to blockade of the renin-angiotensin system: a review. Am Heart J 1989;117:756–767. [PubMed]
99. Downham MR, Auton TR, Rosul A, Sharp HL, Sjostrom L, Rushton A, Richards JP, Mant TG, Gardiner SM, Bennett T, Glover JF Evaluation of two carrier protein-angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man. Br J Clin Pharmacol 2003;56:505–512. [PMC free article] [PubMed]
100. Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, Volk HD, Stocker H, Muller P, Jennings GT, Wagner F, Bachmann MF Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet 2008;371:821–827. [PubMed]
101. Brown MJ. Success and failure of vaccines against renin-angiotensin system components. Nat Rev Cardiol 2009;6:639–647. [PubMed]
102. Chen X, Qiu Z, Yang S, Ding D, Chen F, Zhou Y, Wang M, Lin J, Yu X, Zhou Z, Liao Y Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals. Hypertension 2013;61:408–416. [PubMed]
103. Kenny AJ, Bourne A, Ingram J Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C-type natriuretic peptide and some C-receptor ligands by endopeptidase-24.11. Biochem J 1993;291(Pt 1):83–88. [PubMed]
104. Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet 2010;375:1255–1266. [PubMed]
105. Kario K, Tamaki Y, Okino N, Gotou H, Zhu M, Zhang J LCZ696, a first-in-class angiotensin receptor-neprilysin inhibitor: the first clinical experience in patients with severe hypertension. J Clin Hypertens (Greenwich) 2016;18:308–314. [PubMed]
106. Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J 2015;36:1967–1973. [PubMed]
107. El Andalousi J, Li Y, Anand-Srivastava MB Natriuretic peptide receptor-C agonist attenuates the expression of cell cycle proteins and proliferation of vascular smooth muscle cells from spontaneously hypertensive rats: role of Gi proteins and MAPkinase/PI3kinase signaling. PLoS ONE 2013;8:e76183. [PMC free article] [PubMed]
108. Kelly JP, Mentz RJ, Hasselblad V, Ezekowitz JA, Armstrong PW, Zannad F, Felker GM, Califf RM, O'Connor CM, Hernandez AF Worsening heart failure during hospitalization for acute heart failure: insights from the acute study of clinical effectiveness of nesiritide in decompensated heart failure (ASCEND-HF). Am Heart J 2015;170:298–305. [PMC free article] [PubMed]
109. van Deursen VM, Hernandez AF, Stebbins A, Hasselblad V, Ezekowitz JA, Califf RM, Gottlieb SS, O'Connor CM, Starling RC, Tang WH, McMurray JJ, Dickstein K, Voors AA Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF). Circulation 2014;130:958–965. [PubMed]
110. Suzuki Y, McMaster D, Lederis K, Rorstad OP Characterization of the relaxant effects of vasoactive intestinal peptide (VIP) and PHI on isolated brain arteries. Brain Res 1984;322:9–16. [PubMed]
111. Yin J, Wang L, Yin N, Tabuchi A, Kuppe H, Wolff G, Kuebler WM Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25–1553 in murine and rat lungs. PLoS ONE 2013;8:e75861. [PMC free article] [PubMed]
112. Couvineau A, Laburthe M VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol 2012;166:42–50. [PMC free article] [PubMed]
113. Acra S, Ghishan FK Increased Na(+)-H+ exchange in jejunal brush border membrane vesicles of spontaneously hypertensive rats. Gastroenterology 1991;101:430–436. [PubMed]
114. Labonte ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Dy E, Black D, Zhong Z, Langsetmo I, Spencer AG, Bell N, Deshpande D, Navre M, Lewis JG, Jacobs JW, Charmot D Gastrointestinal inhibition of sodium-hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD. J Am Soc Nephrol 2015;26:1138–1149. [PubMed]
115. Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med 2014;6:227ra36. [PubMed]
116. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128. [PubMed]
117. Almeida L, Nunes T, Costa R, Rocha JF, Vaz-da-Silva M, Soares-da-Silva P Etamicastat, a novel dopamine beta-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension. Clin Ther 2013;35:1983–1996. [PubMed]
118. Padmanabhan S, Caulfield M, Dominiczak AF Genetic and molecular aspects of hypertension. Circ Res 2015;116:937–959. [PubMed]
119. Padmanabhan S, Graham L, Ferreri NR, Graham D, McBride M, Dominiczak AF Uromodulin, an emerging novel pathway for blood pressure regulation and hypertension. Hypertension 2014;64:918–923. [PubMed]
120. Lynch AI, Boerwinkle E, Davis BR, Ford CE, Eckfeldt JH, Leiendecker-Foster C, Arnett DK Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. J Am Med Assoc 2008;299:296–307. [PubMed]
121. Zhang Y, Li H, Zhou J, Wang A, Yang J, Wang C, Liu M, Zhou T, Zhu L, Zhang Y, Dong N, Wu Q A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity. Sci Rep 2014;4:7378. [PMC free article] [PubMed]
122. Amador CA, Barrientos V, Pena J, Herrada AA, Gonzalez M, Valdes S, Carrasco L, Alzamora R, Figueroa F, Kalergis AM, Michea L Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes. Hypertension 2014;63:797–803. [PubMed]
123. McMaster WG, Kirabo A, Madhur MS, Harrison DG Inflammation, immunity, and hypertensive end-organ damage. Circ Res 2015;116:1022–1033. [PMC free article] [PubMed]
124. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM, American Heart Association. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension 2006;47:296–308. [PubMed]
125. Macready AL, George TW, Chong MF, Alimbetov DS, Jin Y, Vidal A, Spencer JP, Kennedy OB, Tuohy KM, Minihane AM, Gordon MH, Lovegrove JA,FLAVURS Study Group. Flavonoid-rich fruit and vegetables improve microvascular reactivity and inflammatory status in men at risk of cardiovascular disease – FLAVURS: a randomized controlled trial. Am J Clin Nutr 2014;99:479–489. [PubMed]
126. Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, Settler U, Plachta-Danielzik S, Wagner AE, Frank J, Schrezenmeir J, Rimbach G, Wolffram S, Muller MJ Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr 2009;102:1065–1074. [PubMed]
127. Devireddy CM, Bates MC Experience with an innovative new Food and Drug Administration pathway for first-in-human studies: carotid baroreceptor amplification for resistant hypertension. JACC Cardiovasc Interv 2014;7:1328–1330. [PubMed]
128. Spiering W, Van Der Heyden J, Devireddy C, Foster MT III, Bates MC, Kroon AA Lb02.05: controlling and lowering blood pressure with the Mobiushd device: first-in-man results (Calm-Fim study). J Hypertens 2015;33 (Suppl. 1):e86. [PubMed]
129. O'Callaghan EL, McBryde FD, Burchell AE, Ratcliffe LE, Nicolae L, Gillbe I, Carr D, Hart EC, Nightingale AK, Patel NK, Paton JF Deep brain stimulation for the treatment of resistant hypertension. Curr Hypertens Rep 2014;16:493. [PubMed]
130. Green AL, Wang S, Bittar RG, Owen SL, Paterson DJ, Stein JF, Bain PG, Shlugman D, Aziz TZ Deep brain stimulation: a new treatment for hypertension? J Clin Neurosci 2007;14:592–595. [PubMed]
131. Patel NK, Javed S, Khan S, Papouchado M, Malizia AL, Pickering AE, Paton JF Deep brain stimulation relieves refractory hypertension. Neurology 2011;76:405–407. [PMC free article] [PubMed]
132. Plachta DT, Gierthmuehlen M, Cota O, Espinosa N, Boeser F, Herrera TC, Stieglitz T, Zentner J Blood pressure control with selective vagal nerve stimulation and minimal side effects. J Neural Eng 2014;11:036011. [PubMed]
133. Mahfoud F, Böhm M, Azizi M, Pathak A, Durand Zaleski I, Ewen S, Tsioufis C, Andersson B, Blankestijn PJ, Burnier M, Chatellier G, Gafoor S, Grassi G, Joner M, Kjeldsen SE, Lüscher TF, Lobo MD, Lotan C, Parati G, Redon J, Ruilope L, Sudano I, Ukena C, Leeuwen E, Volpe M, Windecker S, Witkowski A, Wijns W, Zeller T, Schmieder RE Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. European Heart Journal 2015;36:2219–2227. [PubMed]

Articles from European Heart Journal are provided here courtesy of Oxford University Press