Percutaneous Renal Sympathetic Denervation: 2013 and Beyond

Canadian Journal of Cardiology 30 (2014) 64e74

Review

Percutaneous Renal Sympathetic Denervation: 2013 and Beyond Michael Froeschl, MD, MSc,a Adnan Hadziomerovic, MD,b and Marcel Ruzicka, MD, PhDc a

Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada b c

Department of Diagnostic Imaging, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada

Division of Nephrology, Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada

ABSTRACT

  RESUM E

Systemic hypertension affects almost a quarter of Canadian adults. Although most can achieve adequate blood pressure control using a combination of medical and lifestyle interventions, many have resistant hypertension and are unable to reach their target. Percutaneous renal sympathetic denervation has been developed to address a crucial mechanism in the pathophysiology of hypertension: renal sympathetic overactivity. In 2009, the first-in-man experience with renal denervation was published. Several studies followed, including the randomized Symplicity HTN-2 trial of 106 patients: 6-month mean blood pressure reduction was 32/12 mm Hg in those who underwent renal denervation, vs a change of þ1/0 Hg in those who did not. However, all the evidence to date suffers from the same drawbacks: studies are small, and follow-up is short and largely incomplete. The future of renal denervation will be determined by 3 factors. First, there

mique touche presque le quart des adultes caL’hypertension syste ussir à maîtriser nadiens. Bien que la plupart puissent re quatement leur pression arte rielle par une combinaison d’interade dicales et de changements au mode de vie, plusieurs ont ventions me sistante et sont incapables d’atteindre leur objecune hypertension re nervation sympathique re nale par voie percutane e a e  te  tif. La de veloppe e pour reme dier à un important me canisme physide  excessive sympathique opathologique de l’hypertension : l’activite nale. La première expe rience de de nervation re nale chez l’homme re  te  publie e en 2009. Plusieurs e tudes l’ont suivie, dont l’essai a e atoire Symplicity HTN-2 comportant 106 patients : la diminution ale rielle après 6 mois a e  te  de 32/12 mm Hg moyenne de la pression arte nervation re nale par rapport à un chez ceux qui avaient subi la de changement de þ 1/0 mm Hg chez ceux qui ne l’avaient pas subie.

On March 28, 2012, the first percutaneous renal sympathetic denervation (RSD) system received a Health Canada license for use.1 The indication for which approval was granted was the treatment of uncontrolled resistant hypertension. The decision to approve the device was based on the results of 3 studies that included a total of 205 patients who underwent RSD as a treatment for uncontrolled resistant hypertension.1,2-4 As of September 2013, there is still only 1 RSD system available for clinical use in Canada. This article is divided into 4 parts. The first reviews the epidemiology of hypertension and the physiological basis behind RSD as a potential treatment. The second explores the data that support the use of the currently available (in Canada) RSD system in the treatment of resistant hypertension. The third looks ahead, at the promise of new and better evidence for this treatment, at the therapeutic application of this procedure

to other conditions, and at the new forms that this treatment will be taking in the future. The final part of this article provides an update on the current status of RSD in Canada. Despite the novelty of percutaneous RSD, several reviews on the topic have recently been published, including our own in the Training/Practice section of the Canadian Journal of Cardiology (CJC) in the spring of 2013.5 Some of these reviews have focused more on the physiology underlying the mechanism of its treatment effects,6 and others have placed more emphasis on the evolving technology.7 The current article expands on the themes outlined in our previous work and endeavours to provide readers with a broad overview of the subject of RSD. Considering the theme of this edition of the CJC, greater emphasis is placed on the technical and technological aspects of the procedure. Finally, in this rapidly progressing field, this article provides an update on RSD and its clinical utility.

Received for publication July 2, 2013. Accepted November 5, 2013.

Hypertension

Corresponding author: Dr Michael Froeschl, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada. Tel.: þ1-613-761-4049; fax: þ1-613761-5212. E-mail: [email protected] See page 72 for disclosure information.

The clinical burden Hypertension is common: it is estimated that 20%-30% of the world’s adult population contends with elevated blood pressure (BP).8 Recent Canadian data support these numbers:

0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.11.003

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will be more and better evidence. Symplicity HTN-3 has randomized 530 patients to renal denervation vs a sham procedure; 24-hour ambulatory blood pressure monitoring will be assessed in all participants. Other quality trials will follow, including ones that will assess clinical end points. Second, other indications for this treatment will be investigated. Sympathetic overactivity is implicated in many other conditions, including heart failure and arrhythmia; sympathetic denervation might benefit these patients as well. Third, myriad devices, using different methods to achieve renal denervation, are being developed. The first renal denervation system was approved for clinical use in Canada in March 2012. Until more data are available, patients undergoing this procedure should be carefully screened and, ideally, enrolled in research protocols.

es scientifiques obtenues à ce jour Cependant, toutes les donne sentent les mêmes inconve nients : les e tudes sont de petite pre envergure, et le suivi est court et fort incomplet. L’avenir de la nervation re nale sera de termine  par 3 facteurs. Premièrement, il y de es scientifiques plus nombreuses et plus solides. aura des donne  te  re partis L’essai Symplicity HTN-3 comportait 530 patients qui ont e nervation re nale vs une fausse intervention; au hasard pour subir la de rielle des 24 heures sera le monitorage ambulatoire de la pression arte value  chez tous les participants. D’autres essais de qualite  suivront, e valueront les critères cliniques. Deuxièmement, incluant celles qui e tudie es. L’activite  d’autres indications pour ce traitement seront e excessive sympathique est en cause dans plusieurs autres affections, nervation symdont l’insuffisance cardiaque et l’arythmie; la de  ne fique chez ces patients e galement. Troipathique pourrait être be rentes sièmement, le très grand nombre de dispositifs utilisant les diffe thodes pour re aliser la de nervation re nale sont en cours de me veloppement. Le premier système de de nervation re nale a e  te  de  pour utilisation clinique au Canada en mars 2012. Jusqu’à ce approuve es soient disponibles, les patients qui subiront que davantage de donne lectionne s et ide alecette intervention devront être soigneusement se ment être inscrits aux protocoles de recherche.

in 2007-2008, 6 million Canadian adults, or 23% of the adult population, were suffering from chronic hypertension.9 Furthermore, hypertension is dangerous: it is a major risk factor for coronary artery disease, heart failure, stroke, and chronic kidney disease.10,11 Considering these 2 simple facts, it should not be surprising that hypertension is the leading risk factor for global disease burden, accounting for 7% of disability-adjusted life years world-wide.12 Various pharmacotherapies developed during the past century have provided countless hypertensive patients substantial benefit, in terms of prevention of end-organ damage and premature death. Unfortunately, many patients with chronic hypertension suffer from so-called resistant hypertension: BP that remains above target despite the use of 3 or more antihypertensive drugs, including a diuretic, at optimal doses.13 Estimates of the prevalence of resistant hypertension vary widely. Some sources suggest that as many as 30% of patients with chronic hypertension contend with resistant hypertension,14 although a lower prevalence, on the order of 10%, might be more realistic.15 The prevalence is likely even lower when pseudo-resistant hypertension, due to nonadherence to treatment or a white coat phenomenon, is rigourously ruled out.16 Data from the Canadian Health Measures Survey support a prevalence of resistant hypertension between 4.4% and 7.8%, depending on the definition used,17 yet the increased morbidity associated with true resistant hypertension is clear. Daugherty and colleagues retrospectively studied 205,750 individuals with a new diagnosis of hypertension. After a median of 1.5 years, 1.9% developed resistant hypertension. Over almost 4 years median follow-up, patients with resistant hypertension suffered significantly higher rates of death or incident myocardial infarction, heart failure, stroke, or chronic kidney disease than did patients with nonresistant hypertension (18.0% vs 13.5%; P < 0.001). After adjustment for confounding factors, the hazard ratio for any cardiovascular event associated with resistant hypertension was 1.47 (95% confidence interval, 1.33-1.62).18

Pathophysiology The kidneys are richly innervated by sympathetic autonomic fibres; they receive no parasympathetic innervations. These norepinephrine-secreting nerves originate in the prevertebral ganglia and travel within the adventitia of the renal arteries to reach their targets within the kidneys. Some fibres terminate within the renal vasculature where stimulation produces vasoconstriction and consequently decreased renal blood and plasma flow and a decreased glomerular filtration rate. Others innervate the granular cells of the juxtaglomerular apparatus and cause the secretion of renin, triggering the reninangiotensin II-aldosterone cascade, and further vasoconstriction and sodium retention by the kidneys. A final group of sympathetic fibres stimulates the cells of the proximal convoluted tubule to reabsorb sodium and water (Fig. 1). All of the above efferent signals from the sympathetic nervous system to the kidneys serve to promote elevation of systemic BP.19 The kidneys also feed back to activate the sympathetic nervous system. They do so primarily via afferent sympathetic fibres that also travel within the adventitia of the renal arteries. These nerves synapse within the spinal cord with others that then transmit signals to autonomic centres within the brain. Sympathetic afferents also run between the 2 kidneys, allowing direct cross-talk between the paired organs. Although all parts of the kidneys are innervated by sympathetic afferent fibres, the greatest concentration of these nerves is found within the renal pelvis.20 There, mechanoreceptors monitor hydrostatic pressure within the urinary collecting system and chemoreceptors detect changes in the oxygen tension of the surrounding renal parenchyma. Finally, it should be emphasized that angiotensin II, a downstream product of renin secretion from the kidney, also exerts a positive feedback effect on the central nervous system, causing a further increase in sympathetic output (Fig. 1). This illustrates the physiologic basis for the role of renal sympathetic activation in the maintenance of chronic hypertension. Experimental evidence also exists. In humans,

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Figure 1. The kidneys’ place within the sympathetic nervous system and the end-organ effects of sympathetic activation. ATII, angiotensin-II.

individuals with chronic hypertension have central sympathetic nervous system overactivity measured by increased muscle sympathetic nerve activity (MSNA).21 Furthermore, renal norepinephrine spillover, a measure of organ-specific (renal) sympathetic nerve activity, is increased in patients with hypertension, and the degree to which it is increased correlates with hypertension severity.20 In dogs, stimulation of the renal sympathetic nerves results in the development of hypertension,22 and in a rat model of high BP, RSD delayed the onset of hypertension and diminished its severity.23 Evidence for the causative role of renal sympathetic activation in hypertension can also be found in the history of medicine. In the 1930s, before the advent of effective and well tolerated pharmacotherapy, renal sympathectomy via surgical splanchnicectomy was advocated as a treatment for severe hypertension.24 The procedure seemed to work: a large, nonrandomized trial of 1266 patients demonstrated a 5-year mortality of 5% in those treated surgically compared with 54% in patients treated medically.25

Unfortunately, the morbidity rate of the procedure was high. Adverse effects of this invasive treatment included often debilitating orthostatic hypotension, excessive sweating, sphincter incompetence resulting in urinary and fecal incontinence, and sexual dysfunction. Surgical renal sympathectomy was essentially abandoned in the 1960s when pharmacotherapy began to establish itself as a viable therapeutic option for patients with hypertension.26 However, in light of the growing global burden of hypertension and its attendant morbidity and mortality, enthusiasm for an albeit less invasive method of RSD has enjoyed a recent renaissance. Current Technology Existing evidence Only 1 RSD system is currently approved for clinical use in Canada: the Symplicity Renal Denervation System

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Figure 2. The Symplicity Renal Denervation System catheter. Reproduced with permission from Medtronic Inc.

(Medtronic, Minneapolis, MN). The Symplicity system consists of a single-electrode radiofrequency (RF) catheter which is attached to a dedicated console (Fig. 2). The ablation catheter fits through a 6-French guiding catheter, which is placed at the ostium of the renal artery using fluoroscopic guidance. The ablation catheter is introduced distally into the renal artery and flexed so as to achieve good apposition to the wall of the renal artery, indicated by a stable impedance displayed on the console. RF energy is then applied over 2 minutes, with a maximum power output of 8 W achieved. This energy produces heat, which creates a thermal injury within the wall of the renal artery. The primary target is the sympathetic nerves within the adventitia of the vessel; injury to the intima is minimized by the cooling effect of the flowing blood, although renal artery wall edema is typically observed during the procedure (Fig. 3). After a first ablation, the catheter is withdrawn proximally by at least 5 mm and usually rotated. After a stable impedance has again been achieved, a second 2-minute RF ablation is applied. Typically, 4-6 ablations are performed within each renal artery. Because of the presence of C-fibres among the renal sympathetic nerves, patients typically experience a diffuse, visceral abdominal pain during the periods of ablation. The discomfort of the procedure is mitigated by generous pretreatment of patients with analgesic and anxiolytic agents, typically narcotics and benzodiazepines, respectively, with top-ups provided as necessary. In 2009, 5 investigators shared their first-in-man experience with RSD in a letter to the editor of the New England Journal of Medicine.27 They described the use of this procedure in a 59-year-old man with uncontrolled hypertension, despite the use of 7 antihypertensive agents. RF ablation was applied to both renal arteries without complication. MSNA decreased from 56 bursts per minute at baseline to 41 bursts per minute at 30 days and 19 bursts per minute at 1 year. Furthermore, from baseline to 30 days, total body norepinephrine spillover decreased by 42%, and renal norepinephrine spillover decreased by 75% and 48% in the right and left

kidney, respectively. Finally, mean office BP decreased from 161/107 mm Hg at baseline to 141/90 at 30 days and 127/81 mm Hg at 1 year, despite the withdrawal of 2 antihypertensive medications. This fall in BP was accompanied by a reduction in left ventricular mass measured using cardiac magnetic resonance imaging. Three clinical studies further supported the benefit of RSD in resistant hypertension and led to approval of the Symplicity device in Canada.1 In 2009, a multicentre safety and proof-ofconcept cohort study of RSD was published,2 followed the next year by a randomized clinical trial.3 The details of these studies, known as Symplicity HTN-1 and Symplicity HTN-2, respectively, are outlined in Table 1. The third study, published in 2011, was an open-label investigation that consisted of the 45 patients treated with RSD in Symplicity HTN-1,2 plus an additional similar 108 patients, for a total “expanded cohort” of 153 patients, followed up to 2 years.4

Figure 3. Still frame of a percutaneous renal sympathetic denervation procedure. The ablation catheter is flexed so that the radio-opaque electrode (arrow) is apposed against the inferior wall of the renal artery. More distally, an indentation into the lumen of the artery is seen at the site of a previous ablation (arrowhead). This is a typical finding after ablation and represents tissue edema.

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Table 1. Outline of the Symplicity HTN-12 and Symplicity HTN-23 studies

Participants Inclusion criteria Exclusion criteria

Number enrolled Patient characteristics Intervention Outcomes Efficacy

Symplicity HTN-1

Symplicity HTN-2

Adults  18 years with office-based systolic BP  160 mm Hg and taking  3 BP medications including a diuretic or drug intolerance  Secondary HTN  eGFR < 45  Type 1 diabetes  Significant valve disease  PPM or ICD  Taking clonidine, moxonidine, rilmenidine, or warfarin  Pregnancy  Renovascular criteria* 50 (45 treated, 5 excluded for anatomical reasons)  Mean age: 58 years  56% male  Mean BP: 177/101 mm Hg  Mean number of drugs: 4.7 Bilateral percutaneous RSD (45 patients)

Adults 18-85 years with office-based systolic BP  160 mm Hg (or  150 mm Hg if diabetic) and taking  3 BP medications including a diuretic or drug intolerance  Secondary HTN  eGFR < 45  Type 1 diabetes  Significant stenotic valve disease  Contraindication to MRI  MI, unstable angina, or stroke within 6 months  Pregnancy  Renovascular criteria* 106  Mean age: 58 years  58% male  Mean BP: 178/97 mm Hg  Mean number of drugs: 5.2 Bilateral percutaneous RSD (treatment, n ¼ 52) vs continued medical management (control, n ¼ 54)

 Mean reduction in norepinephrine spillover: 47%  Mean change in BP (mm Hg): 1 mo: 14/10 (n ¼ 41); 3 mo: 21/10 (n ¼ 39); 6 mo: 22/11 (n ¼ 26); 9 mo: 24/11 (n ¼ 20); 12 mo: 27/17 (n ¼ 9)

Mean change in office BP (mm Hg):

Responder ratey: 84% (RSD) vs 35% (control) Mean change in 24-h ABPM (mm Hg):

Acute safety “Chronic” safety

1 renal artery dissection 1 femoral artery pseudoaneurysm 14- to 30-day angiograms (n ¼ 18): no RAS; 6-month MRA (n ¼ 14): 1 nonobstructive distal side branch irregularity at an area not treated

1 Femoral artery pseudoaneurysm 6 months after RSD renal artery imaging (n ¼ 43): 1 possible progression of atherosclerotic plaque at an area not treated; Mean change in eGFR at 6 months: 0.2 (RSD) vs 0.9 (control); difference in mean change ¼ 0.7 (P ¼ 0.76)

ABPM, ambulatory blood pressure monitoring; BP, blood pressure; eGFR, estimated glomerular filtration rate (mL/min/1.73 m2; calculated according to Modification of Diet in Renal Disease criteria); F/U, follow-up; HTN, hypertension; ICD, implantable cardioverter defibrillator; MI, myocardial infarction; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PPM, permanent pacemaker; RAS, renin-angiotensin II-aldosterone; RSD, renal sympathetic denervation. * Renovascular criteria that excluded patients from participation in these studies: renal artery length < 20 mm or diameter < 4 mm; severe renal artery stenosis; previous renal artery angioplasty or stenting; dual renal artery supply. y Responder rate is the percentage of patients whose systolic BP dropped by at least 10 mm Hg at follow-up, usually at 6 months.

After bilateral RSD, mean BP decreased from 176/98 mm Hg at baseline (for patients taking an average of 5.1 antihypertensive medications) by the following values: 25/11 mm Hg at 6 months; 23/11 mm Hg at 12 months; 26/14 mm Hg at 18 months; and 32/14 mm Hg at 2 years. However, of the 153 patients enrolled in this study, 24-month follow-up data were only available for 18. Procedural complications included 1 renal artery dissection, described previously,2 and 3 femoral artery pseudoaneurysms, one of which was reported previously.2 It should be noted that all 3 of these access site

complications occurred in patients treated with 8-French guiding catheters; the current standard of care for the Symplicity system is delivered via a 6-French guide. Eighty-one patients had noninvasive 6-month renal artery imaging performed. One patient had progression of a pre-existing proximal renal artery atherosclerotic stenosis at a site remote from RF ablation; this was successfully stented. Since the approval of the Symplicity renal denervation system by Health Canada in March 2012, more data supporting its benefits in resistant hypertension emerged. At the

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6-month follow-up in the randomized Symplicity HTN-2 trial, patients in the control group were given the opportunity to crossover and undergo RSD. Of 51 control patients available for assessment at 6 months, 46 chose to have the procedure performed. However, only those with systolic BPs  160 mm Hg at 6 months were included in a BP analysis at 1 year. A further 2 patients were lost to follow-up. Therefore, only 35 patients were analyzed. At 1 year after initial randomization to the control group, and 6 months after crossover to renal denervation, these 35 patients experienced a mean systolic BP drop of 23.7 mm Hg, from 190 mm Hg to 166.3 mm Hg (P < 0.001). Out of the 49 patients originally randomized to renal denervation and available for follow-up at six months, 47 were available for follow-up at 1 year. Systolic BP change at 1 year compared with baseline was 28.1 mm Hg; this was similar to the change documented at 6 months (31.7 mm Hg; P ¼ 0.16).28 In 2013, Symplicity HTN-1, Symplicity HTN-2, and the Symplicity HTN-1 expanded cohort study were included with 9 others in a systematic review and meta-analysis of RSD in resistant hypertension.29 In the 3 studies with a control arm, including Symplicity HTN-1 and Symplicity HTN-2, 6month mean BP decreased by 28.9 mm Hg systolic and 11.0 mm Hg diastolic in patients treated with RSD compared with those treated medically (P < 0.0001 for both). In the 9 uncontrolled studies, 6-month mean BP decreased by 25.0 mm Hg systolic and 10.0 mm Hg diastolic compared with pretreatment values (P < 0.00001 for both). Although the Symplicity catheter was used in two-thirds of the studies, it should be emphasized that there was no significant difference found in the treatment effect among the 5 RSD devices used across the studies. Renal denervation has also demonstrated some clinical benefits beyond lowering BP. In a study of 110 patients, RSD reduced not just BP and aortic pulse pressure, but aortic augmentation, augmentation index, and carotid-to-femoral pulse wave velocity.30 Furthermore, ejection duration and aortic systolic pressure load were also diminished. Another publication has reported on 46 patients who underwent transthoracic echocardiography before and after RSD.31 Left ventricular mass index decreased from 112.4  33.0 g/m2 preprocedure to 103.6  30.5 g/m2 at 1 month after the procedure (P ¼ 0.01) and to 94.9  29.8 g/m2 at 6 months after the procedure (P < 0.001). Left ventricular diastolic function was also documented to have improved, measured using mitral E-wave deceleration time, isovolumic relaxation time, and tissue Doppler imaging. Furthermore, left ventricular diastolic filling pressures (estimated using lateral E/E prime [E’] measurement) and left atrial size decreased after renal denervation. Finally, left ventricular systolic function improved after the procedure: ejection fraction increased from 63.1  8.1% at baseline to 69.1  7.5% and 70.1  11.5% at 1 and 6 months after the procedure, respectively. This change was mediated by a decrease in end-systolic volumes. Another end point that has been studied in the evaluation of RSD is quality of life. In a small study, 62 patients who underwent renal denervation for uncontrolled resistant hypertension were assessed using questionnaires before the procedure.32 The Medical Outcomes Study 36-Item ShortForm Health Survey (SF-36) was used to establish healthrelated quality of life; the Beck Depression and Spielberger

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State and Trait Anxiety inventories were administered to measure depressive symptoms and anxiety levels, respectively. Forty (65%) of these patients were reassessed using the same tests 3 months after the procedure. No patient suffered a decline on any of the 8 domains of the SF-36. Patients experienced statistically significant improvements in 4 domains: vitality, social function, role emotion, and mental health. This resulted in a significant overall improvement in the Mental Component Summary Scale, 1 of 2 aggregated components of the SF-36. Three months after renal denervation, patients also saw improvement in their Beck Depression Inventory scores, benefiting from ameliorations in sadness, tiredness, and libido. There was no significant change in state or trait anxiety levels. The authors note that there was no association between the improved quality of life and depression scores and the magnitude of BP reduction achieved. Three final RSD end points have been assessed, albeit indirectlydby means of modelling: cardiovascular morbidity and mortality, and cost effectiveness.33 A state-transition (Markov) model was developed to project the clinical effect of RSD using the Symplicity system on top of standard-ofcare treatment. Clinical end points considered included: stroke, myocardial infarction, all coronary heart disease, heart failure, end-stage renal disease, cardiovascular mortality, and all-cause mortality. The model thus created predicted a decrease in all 7 end points at 10 years and lifetime. Median survival was predicted to increase from 17.07 to 18.37 years, and quality-adjusted life expectancy was predicted to increase from 12.07 to 13.17 years. The discounted lifetime incremental cost-effectiveness ratio was calculated at USD$2715 per life-year gained and USD$3071 per quality-adjusted life-year gained. Considering that USD$50,000 per qualityadjusted life-year is widely considered the incremental costeffectiveness ratio threshold under which medical and surgical therapies are considered acceptable from a societal perspective, renal denervation is predicted to be a costeffective treatment for hypertension. Limitations to and gaps in the evidence Despite the encouraging results presented herein, there are several important limitations to and gaps in the available evidence for RSD as a treatment for resistant hypertension. Critics of the role of RSD in patient care express their concerns in 2 simple questions: how well does RSD really work, and how certain is its safety? Concerns about the true efficacy of RSD are based on limitations to the evidence that support the procedure, and on new evidence that seems to challenge it. There are many issues with the current data. First, the number of patients studied to date is very small. Symplicity HTN-2, the only randomized trial using this technology, enrolled only 106 patients3; and the recent systematic review and meta-analysis of RSD, described earlier and which included Symplicity HTN-2, studied only 561 patients.28 Furthermore, many of the studies identified by the authors of the systematic review as potentially of interest were excluded because they overlapped with others in terms of the patients involved. For example, the beneficial effects of RSD on pulse wave velocity30 and echocardiography,31 reviewed herein, were documented in patients

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participating in Symplicity HTN-2.3 Second, the follow-up of patients included in trials has been quite short and rather incomplete. BP data from the Symplicity HTN-2 study are only available out to 30 months, and only in abstract form.34 Moreover, although the BP reductions after the procedure do seem durable (systolic and diastolic values were reduced by 35 and 13 mm Hg, respectively, at 30 months compared with baseline), these data are based on only 37 of the 49 patients assessed at 6 months. Longer-term follow-up of treatment efficacy is warranted because reinnervation after RSD is a distinct possibility. This phenomenon has been documented in animals, in as little as 8 weeks after renal sympathectomy.35 Reinnervation has also been observed in humans after kidney transplant, although the potential for renal efferent reinnervation appears considerably greater than that for renal afferent reinnervation.36 Third, in the major trials of RSD presented herein, pseudoresistant hypertension was not systematically ruled out. There was no rigourous assessment of patients’ adherence to their medical regimen. The importance of drug adherence in resistant hypertensiondand the challenge of measuring and managing this problemdhave been detailed in a recent review.37 Our own experience with RSD supports the use of direct observation therapy (ie, witnessed intake of antihypertension medications), as part of the patient selection process.38 Furthermore, 24-hour ambulatory BP monitoring (ABPM) was not consistently used to rule out a white coat effect. A recent study by Mahfoud and colleagues39 documented that patients with high office-based BP but normal BP on 24-ABPM benefited from RSD only in terms of officebased BP, and ambulatory BP did not decrease significantly. This emphasizes the importance of also using ABPM as an outcome measure. Fourth, the medical management of patients enrolled in RSD trials has been criticized.40 For example, mineralocorticoid receptor antagonists, which have evidence of benefit in patients with resistant hypertension,41 were only used in a minority of patients treated with renal denervation in the Symplicity HTN-2 randomized trial and the Symplicity HTN-1 registry (17% and 22%, respectively).3,4 Fifth, all patients treated with RSD in the studies published to date were unblinded to their treatment. The very real influence of a placebo effect must be considered; the fact that outcomes assessors also were not blinded as to their patients’ treatment allows for the introduction of important bias. Finally, the discrepancy between office readings and ABPM as measures of RSD benefit is cause for concern. This is especially so in light of predictions, based on trends in BPlowering seen in drug trials, that the absolute values for officebased BP reduction will approach those for ABPM with the advent of patient blinding in RSD studies.42 There is also some more recent data that challenge the true efficacy of RSD. One mechanism by which RSD is believed to reduce BP is by reducing central sympathetic output. Indeed, MSNA was decreased after RSD in the first-in-man publication.27 However, 2 recent studies specifically investigating sympathetic output after RSD have yielded conflicting results.43,44 Another publication assessed the efficacy of RSD in patients in whom medication nonadherence had been definitively ruled out.45 This was done by performing ABPM after direct observation therapy. No change in mean BP was observed at 1, 3, or 6 months after RSD. However, it should be emphasized that the study included only 6 patients.

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Furthermore, 2 patients did derive a BP benefit after RSD, measured in the office and using ABPM. Finally, a recent study of 109 patients with essential hypertension screened with ABPM at 10 European hypertension centres demonstrated BP reductions at 6 months that were considerably lower than previously reported: 17.6/7.1 mm Hg in the office and 5.9/3.5 mm Hg using ABPM (P  0.03 for both).46 Crucial questions also remain to be answered where the safety of RSD is concerned. In the studies performed to date, acute procedural injury to the renal artery has been rare. However, that might depend on how carefully one looks: when using optical coherence tomography to assess the renal arteries after RSD, small cavities and small thrombi can be seen at the sites of RF delivery.47 In general, 6-month imaging of the renal arteries after RSD in clinical studies has proved reassuring, but cases of renal artery stenosis within 6 months of RF ablation have been reported.48,49 Furthermore, autopsies in animals 6 months after denervation have demonstrated intimal thickening, medial and adventitial fibrosis, and disruption of the external elastic lamina of the renal arteries.50 Although no stenoses were observed, these histological changes could conceivably come with future consequences. Finally, it remains to be seen what the long-term consequences of RSD will be on the body as a whole. If the kidneys’ input and output to sympathetic activation is permanently disrupted, might a person’s compensatory physiologic response to severe stress, such as hemorrhagic or septic shock, be attenuated? The answer to this question is not presently available. However, it is reassuring that under similar, albeit less stressful, circumstances of physical stress (cardiopulmonary exercise testing), RSD does not seem to affect either heart rate response or oxygen uptake, despite decreases in BP at rest, during stress, and during recovery.51 A Look Ahead In our previous brief review of RSD,5 we argued that the future of this technology will be determined by 3 developments. This section expands on those ideas. The first development relates to the concept of RSD as a treatment for resistant hypertension: more and better evidence. In September 2011, the multicentre Symplicity HTN-3 trial (ClinicalTrials.gov Identifier NCT01418261) began enrolling patients. This industry-sponsored study endeavours to confirm the efficacy and safety of RSDdspecifically with the use of the Symplicity systemdas a treatment for uncontrolled resistant hypertension.52 The trial also aims to address several concerns about the evidence available to date. First, the trial will enroll considerably more patientsdapproximately 530 in alldthan any study performed so far. Second, patients will be blinded to their treatment allocation: those in the treatment arm will undergo RSD, and those in the control arm will undergo a sham procedure. Outcomes assessors, too, will be blinded. Third, all participants will have gold-standard BP assessment performed: 24-hour ABPM. Before the start of the study, patients with a systolic average < 135 mm Hg will be excluded from participation, and 24-hour ABPM is a secondary end point that will be measured in all participants. Countless other studies, testing Symplicity and other RSD devices, will follow. The most important of these is the planned EnligHTNment trial. This would be the largest randomized clinical trial of

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Table 2. Comparisons of the 6 renal sympathetic denervation systems currently approved for clinical use in Europe Device (Company) Symplicity (Medtronic Inc)

Date of Conformite Europeene Mark

Ablation modality

April 2010

Specifications

Monopolar radiofrequency Single electrode catheter; Not advanced over a guidewire PARADISE (ReCor December 2011 and Ultrasound Ultrasound transducer within a fluid-filled Medical Inc) January 2013 (first and second balloon; generations, respectively) Advanced over a guidewire OneShot (Covidien-Maya) February 2012 Monopolar radiofrequency Helical electrode on an irrigated balloon catheter; Advanced over a guidewire EnligHTN (St Jude Medical) May 2012 and Monopolar radiofrequency 4-electrode, nonocclusive basket; First and second generations August 2013 (first and second Not advanced over a guidewire; generations, respectively) Second-generation device allows for simultaneous as opposed to sequential ablations Vessix Renal Denervation May 2012 Bipolar radiofrequency 4-8 bipolar electrodes on a noncompliant balloon; System (Boston Scientific Advanced over a guidewire Corp) Iberis System (Terumo) April 2013 Monopolar radiofrequency Single electrode catheter; Not advanced over a guidewire; 2 catheters, for radial and femoral artery access

Clinical trial program(s) Symplicity HTN REALISE RAPID EnligHTN EnligHTNment REDUCE-HTN Iberis-HTN

RAPID, Rapid Renal Sympathetic Denervation for Resistant Hypertension; REALISE, Renal Denervation by Ultrasound Transcatheter Emission; REDUCEHTN, Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transluminal Angioplasty Catheter.

RSD ever conducted, testing the efficacy and safety of the EnligHTN Renal Denervation System (St Jude Medical, St Paul, MN; described later in text) in approximately 4000 hypertensive patients at 150 centres around the world. Furthermore, the primary end point of the study will be major adverse cardiovascular events, including myocardial infarction, stroke, heart failure hospitalizations, and cardiovascular death. Patient follow-up will be over 5 years. The second development that will shape the future of RSD is a potential expansion of the indications for the procedure. If renal denervation decreases pathologically elevated sympathetic nervous system activation of the kidneys, it could prove beneficial in other conditions where sympathetic tone is pathologically elevated (Fig. 1). The most obvious target disease state for any cardiologist is heart failure. A small study of 7 patients demonstrated the safety of renal denervation in patients with chronic heart failure.53 Mean BP at the time of referral was 112/65 mm Hg. There were no significant reductions in BP 6 months after RSD, and there were no instances of hypotensive or syncopal episodes. There were also no changes in renal function. Patients did experience a significant increase of 27.1  9.7 m in the 6-minute walk distance at 6 months (P ¼ 0.03). Larger studies of renal denervation in patients with chronic heart failure are currently under way (eg, Renal Artery Denervation in Chronic Heart Failure Study [REACH], ClinicalTrials.gov Identifier NCT01639378; Symplicity-HF, ClinicalTrials.gov Identifier NCT01392196). Arrhythmias constitute another important cardiac problem in which a reduction in sympathetic output might prove beneficial. Renal denervation has been studied in patients with uncontrolled resistant hypertension undergoing atrial fibrillation (AF) ablation.54 Not surprisingly, patients randomized to denervation after AF ablation enjoyed significant reductions in systolic and diastolic BP, but these patients also experienced less recurrent AF. At 12 months after pulmonary vein isolation, 9 out of 13 patients (69%) who received renal denervation after AF ablation were free of AF, compared with only 4 out of 14 patients (29%) who had AF ablation alone (P ¼ 0.033). There is also anecdotal evidence for the benefit of renal denervation in the treatment of

ventricular arrhythmias.55 Finally, small studies have suggested a beneficial effect of RSD on insulin sensitivity56 and on obstructive sleep apnea syndrome.57 The final development in the story of RSD will centre on the technology itself. Although only 1 device is currently approved in Canada, and none are approved in the United States, no fewer than 6 renal denervation systems have received the Conformite Europeene mark in Europe as of September 2013 (Table 2). Five of these devicesdSymplicity, EnligHTN, Vessix Renal Denervation System (Boston Scientific Corp, Natick, MA), OneShot (Covidien-Maya, Mansfield, MA), and Iberis System (Terumo, Somerset, NJ, USA)duse RF energy to disrupt the sympathetic fibres in the walls of the renal arteries. The sixth devicedPARADISE (ReCor Medical Inc, Menlo Park, CA)duses ultrasound energy. Each of the newer devices aims to improve on the first-generation Symplicity system in 1 or more ways. The major advantage shared among most of these newer technologies is the ability to deliver ablation energy to nerves in different parts of the renal artery at the same time. This is achieved either through a circumferential application of ultrasound (PARADISE); a spiral application of RF (OneShot); or the use of multiple RF electrodes (EnligHTN and Vessix). This important advance results in shorter procedure times, less radiocontrast and radiation use, less patient discomfort, and less reliance on operator ability. It should be of no surprise that a second-generation Medtronic device, Symplicity Spyral, has already been launched. With 4 monopolar electrodes on a spiral ablation catheter, it also allows for the simultaneous application of RF energy to separate areas of the renal artery. Other novel strategies are actively being developed to denervate the kidneys. These include the injection of a guanethedine into the renal artery adventitia via a microneedle deployed from a catheter in the lumen (Bullfrog microinfusion catheter; Mercator MedSystems Inc, San Leandro, CA). A similar chemical approach, this time using ethanol, has also been successfully used, but the application was directly percutaneous and guided by magnetic resonance imaging, as opposed to transluminal.58 Finally, the feasibility of an

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Figure 4. The EnligHTN Renal Denervation System catheter. Reproduced with permission from St Jude Medical, Inc.

entirely noninvasive renal denervation, using extracorporeal high-intensity focused ultrasound, has recently been demonstrated.59 Of these RSD challengers to the Symplicity system, the most mature technology lies in the EnligHTN device. The EnligHTN catheter has 4 monopolar electrodes, each one located in a staggered fashion on an expandable basket (Fig. 4). This allows for easier apposition of the electrode against the wall of the renal artery and more reliable spatial separation of ablation lesions. One disadvantage of this system in its current form is that it requires delivery via an 8-French catheter. Data supporting the efficacy and safety of the EnligHTN system come from the recently published EnligHTN-1 trial.60 Forty-six patients with uncontrolled resistant hypertension were treated with sympathetic renal denervation using the EnligHTN system. Mean office BP was reduced from 176/96 mm Hg preprocedure to 150/86 mm Hg at 6 months after the procedure (mean BP reduction of 26/10 mm Hg; P < 0.001). The responder rate was 80%. One-year results of this trial were recently presented: average systolic BP reduction at that time point was 27 mm Hg.61 RSD: Current State of the Art, Including in Canada As was mentioned at the very outset of this article, the first percutaneous RSD technology was approved by Health Canada in the spring of 2012. The device is approved for use in patients with office systolic BP of at least 160 mm Hg (or at least 150 mm Hg in patients with type 2 diabetes) taking 3 or more BP-lowering drugs, including a diuretic. Although there are no absolute contraindications for the device listed in Health Canada’s Summary Basis of Decision, several warnings are mentioned, including estimated glomerular filtration rate < 45 mL/min/1.73 m2, renovascular abnormalities, and previous renal artery angioplasty or stenting.1 In April 2013, the European Society of Cardiology published an expert consensus document on catheter-based renal denervation.62 In it, the authors support the clinical use of RSD in patients whose systolic BP is  160 mm Hg (or  150 mm Hg in diabetic patients) despite treatment with at least 3 antihypertensive medications from different classes, at

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optimal doses, and including a diuretic. They even note that at certain centres, a BP cutoff of 140 mm Hg is used. The authors do emphasize that candidates for the procedure require an evaluation at a hypertension centre of excellence where primary hypertension is confirmed and pseudoresistant hypertension is ruled out. Finally, the authors also recommend that clinicians follow the same exclusion criteria established in the Symplicity trials. Very similar recommendations were recently made by a global panel of hypertension experts, many of whom also coauthored the European consensus document.63 In Canada, most if not all RSD programs have indeed been initiated as a collaboration between proceduralists and hypertension specialists. The former include interventional cardiologists, interventional radiologists, and/or vascular surgeons. Rooting a renal denervation program in a hypertension clinic ensures thoughtful preprocedure patient evaluation and thorough patient follow-up after the procedure. Outside of a research protocol, RSD should be reserved for individuals identified by a hypertension specialist as having true uncontrolled resistant hypertension. For those few patients truly intolerant of pharmacotherapy, RSD can also be considered on compassionate grounds, but this strategy has not been formally evaluated. Considering the still limited data supporting RSD in resistant hypertension, let alone in other indications, patients receiving this treatment should ideally be included in a research protocol. One such study is the multicentre Pragmatic Randomized Clinical Evaluation of Renal Denervation for Treatment-Resistant Hypertension (PaCE) trial (ClinicalTrials.gov Identifier NCT01895140). PaCE will randomize 104 patients with uncontrolled resistant hypertension across Ontario to either early or late RSD. The primary outcome will be mean 24-hour ABPM at 6 months. Secondary outcomes will include medication intensity, quality of life, and several safety measures. A cost-effectiveness analysis will also be performed. A unique aspect of this study is that to be considered for inclusion, patients require referral by a hypertension expert. In this sense, PaCE will test the feasibility of RSD performed by a multidisciplinary team within a context of resistant hypertension treatment provided by dedicated hypertension specialists. Six-month data are expected by the fall of 2014. Conclusions Sympathetic nervous system activation is a key component in the pathophysiology of chronic hypertension. Percutaneous RSD appears to interrupt this neurohormonal overactivity. The first RSD technology is currently available to Canadian physicians and their patients. The data supporting the use of renal denervation in the treatment of uncontrolled resistant hypertension, and perhaps other conditions in which neurohormonal activation figures prominently, are at least intriguing and at best promising. However, before this procedure is applied widely, a great deal more about it needs to be learned. Disclosures Dr Froeschl has received an honorarium and reimbursement of travel expenses from Medtronic related to education regarding RSD and the Symplicity Renal Denervation System.

Froeschl et al. Percutaneous Renal Sympathetic Denervation

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Drs Hadziomerovic and Ruzicka have no conflicts of interest to disclose.

18. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012;125: 1635-42.

References

19. Koepke JP, DiBona GF. Functions of the renal nerves. Physiologist 1985;28:47-52.

1. Health Canada. Summary Basis of Decision (SBD) for Symplicity Renal Denervation System. Available at: http://www.hc-sc.gc.ca/dhp-mps/ prodpharma/sbd-smd/md-im/sbd_smd_2012_symplicity_189954-eng. php. Accessed May 27, 2013.

20. DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010;298: R245-53.

2. 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.

21. Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA. Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens 2004;17:217-22.

3. Symplicity HTN-2 Investigators, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 2010;376:1903-9. 4. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911-7. 5. Froeschl M, Hadziomerovic A, Ruzicka M. Renal sympathetic denervation for resistant hypertension. Can J Cardiol 2013;29:636-8. 6. Bertog SC, Sobotka PA, Sievert H. Renal denervation for hypertension. JACC Cardiovasc Interv 2012;5:249-58. 7. Bunte MC, Infante de Oliveira E, Shishehbor MH. Endovascular treatment of resistant and uncontrolled hypertension: therapies on the horizon. JACC Cardiovasc Interv 2013;6:1-9. 8. Staessen JA, Kuznetsova T, Stolarz K. Hypertension prevalence and stroke mortality across populations. JAMA 2003;289:2420-2. 9. Robitaille C, Dai S, Waters C, et al. Diagnosed hypertension in Canada: incidence, prevalence and associated mortality. CMAJ 2012;184:E49-56. 10. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-74.

22. Kottke FJ, Kubicek WG, Visscher MB. The production of arterial hypertension by chronic renal artery-nerve stimulation. Am J Physiol 1945;145:38-47. 23. Abramczyk P, Zwolinska A, Oficjalski P, Przybylski J. Kidney denervation combined with elimination of adrenal-renal portal circulation prevents the development of hypertension in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1999;26:32-4. 24. Page IH, Heuer GJ. A surgical treatment of essential hypertension. J Clin Invest 1935;14:22-6. 25. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1266 cases. J Am Med Assoc 1953;152:1501-4. 26. 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. 27. Schlaich M, Sobotka PA, Krum H, Lambert E, Esler M. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Eng J Med 2009;361:932-4. 28. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension. One-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 2012;126: 2976-82. 29. Davis MI, Filion KB, Zhang D, et al. Effectiveness of renal denervation therapy for resistant hypertension. J Am Coll Cardiol 2013;62:231-41.

11. Tozawa M, Iseki K, Iseki C, et al. Blood pressure predicts risk of developing end-stage renal disease in men and women. Hypertension 2003;41:1341-5.

30. Brandt MC, Reda S, Mahfoud F, Lenski M, Böhm M, Hoppe UC. Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension. J Am Coll Cardiol 2012;60:1956-65.

12. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224-60.

31. 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.

13. 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. Circulation 2008;117:e510-26. 14. Pimenta E, Calhoun DA. Resistant hypertension: incidence, prevalence, and prognosis. Circulation 2012;125:1594-6. 15. Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension 2011;57:1076-80. 16. 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. 17. Gee ME, Bienek A, McAlister FA, et al. Factors associated with lack of awareness and uncontrolled high blood pressure among Canadian adults with hypertension. Can J Cardiol 2012;28:375-82.

32. Lambert GW, Hering D, Esler MD, et al. Health-related quality of life after renal denervation in patients with treatment-resistant hypertension. Hypertension 2012;60:1479-84. 33. Geisler BP, Egan BM, Cohen JT, et al. Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol 2012;60:1271-7. 34. Esler M, Krum H, Schlaich M, Schmieder R, Böhm M. Long-term follow-up of catheter-based renal denervation in patients with treatment resistant hypertension: the Symplicity HTN-2 Trial. J Clin Hypertens 2013;15(suppl 1):28. 35. Kline RL, Mercer PF. Functional reinnervation and development of supersensitivity to NE after renal denervation in rats. Am J Physiol 1980;238:R353-8. 36. DiBona GF. Renal innervations and denervation: lessons from renal transplantation reconsidered. Artif Organs 1987;11:457-62.

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37. Burnier M, Wuerzner G, Struijker-Boudier H, Urquhart J. Measuring, analyzing, and managing drug adherence in resistant hypertension. Hypertension 2013;62:218-25.

51. Ukena C, Mahfoud F, Kindedrmann I, et al. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol 2011;58:1176-82.

38. Ruzicka M, McCormick B, Leenen FHH, Froeschl M, Hiremath S. Adherence to blood pressure lowering drugs and resistant hypertension: should trial of direct observation therapy be part of pre-assessment for renal denervation? Can J Cardiol 2013;29:1741.e1-3.

52. Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the Symplicity HTN-3 Trial. Clin Cardiol 2012;35:528-35.

39. Mahfoud F, Ukena C, Schmieder RE, et al. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 2013;128:132-40. 40. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation: ultima ratio or standard in treatment-resistant hypertension. Hypertension 2012;60: 596-606. 41. Vaclavik J, Sedlak R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011;57:1069-75.

53. 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. 54. 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. 55. 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.

42. Howard JP, Nowbar AN, Francis DP. Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials in 4121 patients with focus on trial design: the CONVERGE report. Heart 2013;99:1579-87.

56. 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;123:1940-6.

43. Brinkmann J, Heusser K, Schmidt BM, et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-tocontrol hypertensive patients: prospective case series. Hypertension 2012;60:1485-90.

57. 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.

44. 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.

58. Streitparth F, Walter A, Stolzenburg N, et al. MR-guided periarterial ethanol injection for renal sympathetic denervation: a feasibility study in pigs. Cardiovasc Intervent Radiol 2013;36:791-6.

45. Fadl Elmula FE, Hoffmann P, Fossum E, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure. Hypertension 2013;62:526-32.

59. Wang Q, Guo R, Rong S, et al. Noninvasive renal sympathetic denervation by extracorporeal high-intensity focused ultrasound in a preclinical canine model. J Am Coll Cardiol 2013;61:2185-92.

46. Persu A, Jin Y, Azizi M, et al. Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hypertens 2013. [Epub ahead of print] 47. Cook S, Goy JJ, Togni M. Optical coherence findings in renal denervation. Eur Heart J 2012;33:2992. 48. Kaltenbach B, Id D, Franke JC, et al. Renal artery stenosis after renal sympathetic denervation. J Am Coll Cardiol 2012;60:2694-5.

60. 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. 61. Worthley SG. EnligHTN-1: Safety and Efficacy of a Novel MultiElectrode Renal Denervation Catheter in Patients with Resistant Hypertension: A First-In-Human Multicenter Study. Paris: EuroPCR, 2013.

49. Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure after renal denervation. Lancet 2012;380:778.

62. Mahfoud F, Lüscher TF, Andersson B, et al. Expert consensus document from the European Society of Cardiology on catheter-based renal denervation. Eur Heart J 2013;34:2149-57.

50. Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins CK. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol 2011;100:1095-101.

63. 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;62:2031-45.