|Year : 2014 | Volume
| Issue : 1 | Page : 3-10
Renal sympathetic denervation: A promising therapy for resistant hypertension
Deepak Ameta1, Akshyaya Kumar Pradhan2, Rishi Sethi2
1 Department of Cardiology, Rabindra Nath Tagore Medical College, Udaipur, Rajasthan, India
2 Department of Cardiology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Web Publication||3-Mar-2014|
Akshyaya Kumar Pradhan
Department of Cardiology, King George’s Medical University, Lucknow-226003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Despite rapid strides in pharmacotherapy for hypertension over last few decades, resistant hypertension continues to be prevalent. Activation of the sympathetic nervous system is an important etiological factor in the pathogenesis of hypertension and renal sympathetic nervous system is one of its pivotal arm. Thus, renal sympathetic system was the target of therapy for hypertension in the initial period, in the form of sympathectomy. The major adverse events associated with this procedure and the emergence of potent blood pressure (BP) lowering medications led to disrepute of this procedure. Of late, novel techniques targeting the sympathetic nervous system have emerged. Among them and the most promising one is catheter-based radiofrequency ablation of renal nerves-Renal sympathetic denervation (RSD). Clinical trials of renal denervation therapy have shown consistent and durable reduction of systolic as well as diastolic BP persisting up to 3 years. Beyond BP control, renal denervation also exerts favorable effects on glucose metabolism, heart failure, and sleep apnea. As many as five different catheter-based renal denervation systems are now approved for treating resistant hypertension, the maximum clinical experience being with Medtronic's symplicity system. The European Society of Cardiology guidelines for hypertension 2013 now recommend catheter-based renal denervation for management of drug-resistant hypertension. In this review, we briefly discuss the role of sympathetic nervous system in the pathogenesis of hypertension, the present status, and future perspectives of RSD in the treatment of resistant hypertension.
Keywords: Radiofreqyency ablation, resistant hypertension, renal denervation, sympathetic system, symplicity
|How to cite this article:|
Ameta D, Pradhan AK, Sethi R. Renal sympathetic denervation: A promising therapy for resistant hypertension. Heart India 2014;2:3-10
| Introduction|| |
Hypertension remains one of the most important noncommunicable diseases in the present era. The number of adults with hypertension in 2025 is predicted to increase by about 50% to a total of 1.56 billion (1.54-1.58 billion). , Despite a good armamentarium of anti hypertensive drugs, quite a large number of patients remain undertreated and have poorly controlled blood pressure (BP).
Resistant hypertension is defined as BP that remains above goal (i.e., systolic BP >140 and diastolic BP >90 mm Hg) in spite of the lifestyle modifications and concurrent use of three or more antihypertensive agents, prescribed in optimally targeted dosages, including one diuretic.  Its prevalence is to the order of 20%-30% of all hypertensives and varies by population. , In a recent study of 2,05,750 hypertensive patients followed over 1.5 years, 1.9% developed resistant hypertension.  Such patients are at increased risk of early cardiovascular, renal, and cerebrovascular complications implying the need for strict BP control. Polypharmacy strategies for uncontrolled BP are plagued by numerous problems like pill burden, noncompliance, multiple adverse effects, and increased cost.
The development of novel procedures or devices for resistant hypertension is not necessarily based on the premise of failure of pharmaceutical strategies but rather on the potential of such novel approaches to selectively target organs or nerves without contending with the associated systemic effects of pharmaceutical strategies. These therapies are not being proposed to replace but to supplement existing pharmacotherapies with a goal to achieve safe and cost-effective control of BP.
| Renal Sympathetic Innervation|| |
Both preclinical and human studies involving models of hypertension have convincingly demonstrated the key pathological role of renal sympathetic efferent and afferent nerve activity in the development and progression of hypertension. ,, Their convenient adventitial location makes them amenable for endovascular intervention.
Efferent sympathetic system
The efferent sympathetic fibers of renal sympathetic nervous system originate from the thoracic and lumbar sympathetic trunk [Figure 1]. The postganglionic nerve fibers run alongside the renal artery and enter the hilus of the kidneys and from there they divide into smaller bundles and penetrate the cortical and juxtamedullary area.  Stimulation of efferent nerves leads to renin release, vasoconstriction, and salt water retention. Experimental reduction of efferent renal sympathetic tone in animal model by denervation has been shown to decrease in BP.  The development and severity of hypertension in spontaneously hypertensive rats with sympathetic hyperactivity could be delayed by renal sympathetic denervation (RSD). ,
|Figure 1: Physiological and pathophysiological actions of renal sympathetic nervous system|
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Afferent sympathetic system
The afferent renal nerves are localized predominantly in the pelvic region, the major vessels, and the corticomedullary connective tissue.  The cell bodies of renal afferent nerves lie in the ipsilateral dorsal root ganglia (T6-L4). Afferent renal nerve activation promotes vasopressin and oxytocin release from the neurohypophysis and directly contributes in pathogenesis of systemic hypertension by regulating systemic vascular resistance. ,
Abnormal pathophysiology of essential hypertension is characterized by increased efferent sympathetic drive to the kidneys, as evidenced by elevated rates of renal norepinephrine spill over, defined as the amount of transmitter that escapes neuronal uptake and local metabolism and thus "spills over" into the circulation. Also, there is an increased rate of sympathetic-nerve firing, possibly modulated by afferent signalling from renal sensory nerves. ,,
| Modulation of Sympathetic System for Treatment of Hypertension|| |
Sympathetic nervous system as the target for the treatment of hypertension had previously been explored.
Surgical sympathectomy was introduced in the 4 th and 5 th decades in last century. At that time, effective antihypertensive medications were lacking and the only treatment for the severe hypertension was sympathectomy. This was non selective sympathectomy, often, known as splanchnectomy, as it involved many abdominal visceras. This procedure went into disrepute because, despite being a major operation, the procedure was never complete in terms of total sympathectomy. And also, there were various adverse effects, like, anhidrosis, orthostatic hypotension, orthostatic tachycardia, intestinal disturbances, cold extremities, and erectile dysfunction. ,
Baroreceptor stimulation therapy
This also works on the principle of decreasing sympathetic outflow. An implantable device (Rheos System, CVRx, Inc., Minneapolis, Minnesota.) is used, which stimulates bilateral carotid baroreceptors, decreasing sympathetic activation, thus decreasing heart rate and BP. Initial results were encouraging; however, results of the latest randomized trial were equivocal. , The second-generation device (Barostim neo) has recently become available, which consists of an implantable pulse generator and only one carotid sinus electrode when compared with Rheos system. A trial of 30 patients showed that Barostim neo system in resistant hypertension significantly lowered BP over and above the intensive medical therapy. 
Deep brain stimulation
This concept is based on assumption that deep brain (ventrolateral periaqueductal gray and periventricular gray) stimulation evokes hypotension associated with peripheral vasodilatation indicating a sympathetic inhibition. 
Renal sympathetic denervation
The procedure of sympathectomy has come into light once again with the introduction of catheter-based ablation technique to disrupt both of afferent and efferent renal nervous system.
| Catheter Based Renal Sympathetic Denervation (RSD)|| |
Three major endovascular strategies for RSD-radiofrequency ablation (RFA), ultrasonic ablation; and tissue directed pharmacological ablation are available.  Of the many new percutaneous renal ablation system, five are approved in Europe- Medtronic's Symplicity system, St. Jude's EnligHTN system, Vessix's V2 system, Covidien's One Shot system, and Recor's Paradise system.  All are RFA systems except Recor's ultrasound-based system. The maximum clinical experience is with Symplicity catheter system (discussed here as prototype).
Symplicity renal denervation system
This technique utilizes a RFA catheter (Symplicity® by Medtronic Inc., Minneapolis, MN, USA) which is introduced into each renal artery via femoral arterial access, with the tip of the catheter being placed in the distal renal artery [Figure 2]. Radiofrequency (RF) energy is then applied to the endothelial lining, the catheter is drawn back 1-2 cm, circumferentially rotated, and a further RF energy is applied. This procedure is repeated 4-5 times in the renal artery and then the same RF energy is applied to the contralateral renal artery. During ablation, tip temperature and impedance is monitored by the catheter system altering radiofrequency energy delivery in response to a predetermined algorithm. Significant drop in contact impedance implies adequate ablation. 
|Figure 2: Percutaneous renal denervation procedure with Symplicity catheter system tip in distal renal artery|
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As the procedure is painful sedation is required-midazolam, morphine, or remifentanil can be used. Heparin is given intravenousto achieve an activated clotting time of 250 s. Animal as well as human studies of renal denervation have been shown to produce endothelial damage and thrombus formation. , Hence, expert consensus statements advocate antiplatelet therapy (aspirin) for 4 weeks following the procedure. ,,
Meaningful reductions in BP may take weeks to months to occur implying resetting of sympathetic control. Hence, antihypertensive medications should be continued in postoperative period and titrated subsequently.
| Monitoring and Follow-Up|| |
Office BP should be regularly monitored at 1, 3, 6, 12, 24, and 36 months postprocedure. Apart from this ambulatory and home BP monitoring should also be checked at least at 6, 12, 24, and 36 months. ,, Renal artery imaging by computed tomography scan should be performed at 12 and 36 months following the renal denervation procedure. During follow-up visits, measurement of renal functions is also mandatory (serum creatinine, Estimated Glomerular Filteration Rate (e-GFR), and albuminuria).
| Clinical Experience with Symplicity System|| |
Two clinical trials (SYMPLICITY HTN1 & 2) have assessed the effects of RSD in patients who were resistant to conventional pharmacologic treatment as defined by the failure to achieve systolic BP <160 mm Hg (or <150 mm Hg in patients with diabetes) despite adequate doses of at least three antihypertensive drugs.
SYMPLICITY HTN-1 was an observational first-in-human evaluation of the safety and BP-lowering efficacy of selective RSD in patients with resistant hypertension.  A total of 45 consecutive patients (mean age 58 ± 9 years) with a mean BP of 177/101 ± 20/15 mm Hg were included. Patients were on a mean of 4.7 ± 1.5 antihypertensive drugs. The procedure was associated with significant reduction in both systolic and diastolic office BPs at 1, 3, 6, 9, and 12 months, with mean decreases in office BP of −14/10 ± 4/3, -21/10 ± 7/4, −22/11 ± 10/5, −24/11 ± 9/5, and −27/ 17 ± 16/11 mm Hg, respectively. Radiotracer dilution analyses from 10 patients revealed a substantial reduction in mean NE spillover of 47% (95% confidence interval: 28% to 65%) at 1 month after bilateral denervation [Figure 3]. Muscle sympathetic nerve activity studies suggested a reduction in afferent sympathetic activity, that is, reduced central sympathetic drive [Figure 4]. In 13% of patients, no favorable BP response occurred. Furthermore, at 1-year follow-up, there was evidence of normalization of sympathetic nerve firing rates, accompanied by a reduced left ventricular (LV) mass and a decreased requirement for antihypertensive medication.
|Figure 3: Effects of renal denervation on norepinephrine spillover (Panel A-Renal and Panel B-Whole body) at baseline & 30 days|
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|Figure 4: Effect of renal sympathetic denervation on muscle sympathetic nerve activity over 12 months of follow-up. BP = blood pressure|
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A larger and extended study of the same population (n = 153) demonstrated sustained BP reduction at 2 years.  Baseline values included mean office BP of 176/98 ± 17/15 mm Hg, with a mean of five antihypertensive medications. Postprocedure office BPs were reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months, respectively [Figure 5]. Recently presented 36-month long-term follow-up of this nonrandomized small study confirmed a sustained BP -lowering effect of 33/19 mm Hg (P <0.01, n = 34). 
The study, though not randomized, addressed two major concerns. First, the safety issue, wherein no patient developed renal artery stenosis, barring a single case who had pre-existing renal artery stenosis and had progression of the disease at 6 months, which was successfully stented. No cases of renal artery aneurysm and cholesterol emboli were documented in this series. It is important to note, however, that the RF energy delivered in other conditions is much higher compared with the one required for RSD, thus rendering RSD potentially harmless. Second, durable BP lowering effect up to 3 years demonstrated that the issue of reinnervation is not of clinical relevance. Studies also suugest that, unlike efferent sympathetic fibres, afferent sensory fibers have meagre capacity of regeneration. 
|Figure 5: Mean systolic and diastolic blood pressure changes after renal sympathetic denervation procedure over 24-months of follow-up. Error bars represent 95% confidence interval|
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The SYMPLICITY HTN 2 trial was a multicenter, randomized study of the safety and effectiveness of renal denervation in patients with resistant hypertension.  The primary endpoint was change in office systolic BP at 6 months. A total of 106 patients were randomly allocated to renal denervation (n = 52) or control (n = 54) groups. Office-based BP measurements in the renal denervation group reduced by 32/12 mm Hg, whereas they did not differ from baseline in the control group (change of 1/0 mm Hg). Between group, difference in BP at 6 months was 33/11 mm Hg (P < 0.0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic BP of 10 mm Hg or more, compared with 18 (35%) of 51 controls (P < 0.0001). No serious procedure related or device related complications were noted. The procedure was also showed to be safe in patients with mild-to-moderate impaired renal function. Longer-term follow-up, indicated that even 12 months after the procedure, the mean decrease in office systolic BP in the initial RSD group was similar to the 6-month decrease. 
SYMPLICITY HTN1 was a proof of concept study without control group. SYMPLICTIY HTN 2 study though randomized was not blinded. Both the trials had relatively small sample size and highly selected population groups were enrolled. The follow-up data are available only up to3 years which precludes risk assessment for infrequent or long-term adverse events. Similar to the first study, the Symplicity HTN-2 trial did not clearly define the 'resistant hypertension' either, and did not exclude the possibilities such as secondary hypertension. Only patients with renal arteries with an anatomy favorable to catheter-based therapy (minimal length of 20 mm allowing an adequate landing zone and minimal diameter of 4 mm) were included. ABPM data were not available for all patients and effects of RSD on ambulatory BP monitoring (ABPM) values were less impressive.
SYMPLICITY HTN 3 is large, randomized, single-blinded, multicenter trial currently underway to address some of these concerns.  The inclusion criteria are very similar to those of Symplicity HTN-2, with even more stringent medication requirements. About 530 patients with resistant hypertension will be randomized in a 2:1 ratio to undergo either RSD or a sham procedure. Additionally, all subjects will undergo ABPM.
| Other Novel Potential Renal Denervation Systems|| |
EnligHTN multielectrode renal denervation system
Multielectrode basket design of the EnligHTN catheter (St. Jude Medical Inc., St. Paul, Minnesota, USA) allows for simultaneous energy delivery to four sites along the endoluminalsurface of the artery, with a potential benefit of reducing renal denervation procedural time. EnligHTN-I was first-in-human study was designed to assess the safety and efficacy of this multielectrode ablation system in patients with drug-resistant hypertension.  At 12 months, 80% of patients were responders, 75% had office BP <160 systolic, and 29% had normalized BP.  Average reductions (mm Hg) of office BP at 1, 3, 6, and 12 months were −28/10, −27/10, −26/10, and −27/11 mmHg (P < 0.001), respectively and for 24 h ambulatory BP -10/5, −10/5, and −10/6 mm Hg (P < 0.001).
Vessix V2 renal denervation system
The Vessix V2 renal denervation system (Vessix Vascular Inc., Laguna Hills, California) offers a unique, over-the-wire low-pressure balloon equipped with bipolar RFA electrodes attached to the balloon surface. It offers lower treatment times and can accommodated smaller diameter renal arteries.  Interim data of 139 patients of REDUCE-HTN trial, using Vessix system presented at TCT 2013, demonstrated a significant 24.6 mm Hg reduction in systolic BP (P < 0.0001) at 6 months and sustained 29.6 mm Hg reduction in systolic BP in the subset of patients for whom 12-month data are available. A clinically-meaningful decrease in office BP at both 6 and 12 months was seen in 85% of patients.
One Shot renal denervation system
The One Shot catheter (Maya Medical Inc., Campbell, California, USA) uses an irrigated balloon catheter with a helical electrode on its surface, allowing a single-treatment approach. Preliminary data at 30 days showed that the mean office systolic BP was 155 ± 19 mm Hg, a change of −31 ± 14 mm Hg. 
PARADISE catheter system
The PARADISE (ReCor Percutaneous Renal Denervation System) catheter (ReCor Medical Inc., Ronkonkoma, New York) uses a 6-F ultrasonic balloon catheter and self-centering transducer that delivers a proprietary energy algorithm to circumferentially ablate the renal sympathetic nerves. The REALISE (Renal Denervation by Ultrasound Transcatheter Emission) study is a single-arm, open-label, first-in-man feasibility study of the PARADISE catheter in resistant hypertensive patients with a primary outcome of acute procedural safety. Secondary outcomes include 12-month change ambulatory BP and 12-month change in baseline antihypertensive medication intake. At 3 months average reduction in office and ambulatory BP were −36/17 mmHg and −22/16 mm Hg, respectively. 
It is to noted that all the new devices presented above will have to show favorable safety and efficacy profiles in a larger cohort of patients with subsequent long-term follow-up before a general use can be recommended. 
| Potential Effects of RSD Beyond BP Control|| |
Left ventricular systolic and diastolic parameters
A study of RSD in 64 patients with resistant hypertension showed that it significantly reduced LV mass and improved diastolic function along with significant improvement in BP. The decrement in BP was 22/7 and 28/9 mm Hg at 1 month and 6 months, respectively. The LV mass decreased significantly in treatment group from 112.4 ± 33.9 g/m 2 to 103.6 ± 30.5 g/m 2 at 1 month and to 94.9 ± 29.8 g/m 2 at 6 months (both P < 0.001). There was associated significant improvement in LV end systolic volume and LV ejection fraction. Treatment arm patients also had improvement in diastolic parameters of LV in form of shortening of mitral E wave deceleration time, reduction in isovolumic relaxation time of LV, and improvement in tissue Doppler parameters, like, ratio of mitral inflow velocity to annular relaxation velocity. 
In a study of 50 patients with resistant hypertension by Mahfoud et al.,  RSD resulted in significantly decreased BP along with improvement in glucose metabolism and insulin sensitivity by decreasing insulin and C-peptide levels.
Sleep apnoea activity
RSD also demonstrated an improvement of sleep apnea severity in patients of resistant hypertension and sleep apnoea. 
A pilot study of seven patients with chronic mild to moderate systolic heart failure demonstrated a mild improvement in 6-min walking distance, while ejection fraction and other cardiac structural and functional changes were not changed significantly after 6 months.  RE-ADAPT-CHF, a randomized trial is investigating the effects of renal denervation in 100 patients with chronic heart failure (New York Heart Association functional class II-III).
Chronic kidney disease
Activation of sympathetic system is key to pathophysiology of chronic kidney disease. However, in the Symplicity HTN trials, patients with GFR <45 mL/ min/1.73 m 2 were excluded. In a small series of 15 patients with moderate-to-severe chronic kidney disease, renal denervation was effectively lowered BP without further decline in GFR or effective renal plasma flow 6 months after the procedure.  Office systolic and diastolic BP decreased by 32 ± 18/ 15 ± 12 mm Hg at 6-month follow-up (P < 0.001). Nighttime ambulatory BP was also significantly reduced (P < 0.05). Another proof of concept study of 12 patients with end stage renal disease with uncontrolled BP demonstrated effective reduction of Systolic BP by RSD at 12 months. 
RSD has been shown to significantly reduce the resting heart rate in patients with resistant hypertension and prolonged PR interval.  Also, as a first-in-human experience RSD was used as bailout therapy in two patients with congestive heart failure suffering from treatment-resistant electrical storm.  Pokushalov et al.,  in a recent study of 27 patients reported that RSD reduced AF recurrence when combined with pulmonary vein isolation (PVI).
| Patient Selection and Indications|| |
Based primarily on the results of SYMPLICTY HTN trials, RSD therapy should be offered only to severe treatment resistant hypertension defined as-office systolic BP >160 mm Hg (≥150 mm Hg in type 2 diabetes) despite treatment with at least three antihypertensive drugs of different types in adequate doses, including one diuretic. ,, An ambulatory BP monitoring is mandatory to exclude pseudoresistance. Before embarking upon renal denervation, lifestyle modification, drug compliance, and secondary causes of hypertension should be looked into. Whether it is mandatory for patients should undergo a trial of mineralocorticoid antagonist before RSD is debatable. At present, only patients with preserved renal function (GFR ≥ 45 mL/ min per 1.73 m 2 ) should undergo the procedure.
Two small studied have focused on the role of RSD in moderately resistant hypertension (Systolic BP >140 mmHg, despite three drugs including a diuretic). ,
At 6 months, both studies found office BP reduction in range of 13/5-7 mm Hg. Similar reductions in ambulatory BP recordings were also observed.
For a RSD procedure to be feasible, each renal artery should have a diameter of >4 mm and a length of >20 mm to allow adequate (4-6) application of RF energy. There should be no polar or accessory renal arteries. Contraindications include presence of anatomically significant renal artery abnormalities (e.g., stenosis or fibromuscular dysplasia), previous renal artery interventions, unstable clinical conditions (e.g., acute cardiovascular events),bleeding diathesis, pregnancy, age < 18 years and type 1 diabetes. 
The cost-effectiveness of renal denervation in decreasing long-term cardiovascular morbidity and mortality was recently demonstrated.  The recent ESH/ESC 2013 guidelines for the management of arterial hypertension recommend RSD (Class I) only for truly resistant hypertensive patients, with clinic values ≥160 mm Hg systolic BP or ≥110 mm Hg diastolic BP and with BP elevation confirmed by ambulatory BP monitoring (ABPM). 
| Conclusion|| |
Hypertension is having a global pandemic. Despite adequate pharmacotherapy a substantial number of patients fail to attain target BP goals and are at subsequent risk of cardiovascular events. Modulation of sympathetic system is now emerging as a novel avenue for non pharmacological therapy of hypertension. Catheter-based RFA of renal sympathetic nerves has moved from bench to bedside as safe and cost effective tool for management of resistant hypertension. Evidence from clinical trials has clearly depicted that RSD attains significant and sustained BP lowering effects in resistant hypertension up to 36 months. Apart from BP control RSD also has been shown to be effective in improving glucose homeostasis, sleep apnea, heart failure, arrhythmia, and end-stage renal disease. After the successful trials of prototype Symplicity renal denervation system, four other novel catheter systems are now CE marked in Europe for clinical use. Though at present indicated for severe treatment resistant hypertension (systolic BP >160 mm Hg) with a suitable renal anatomy, data are now merging also for RSD in lesser severe forms of drug resistant hypertension too. The technology for RSD is evolving with persistent endeavor toward making it more easy, safe, and patient friendly. RSD promises to be a one stop and possibly permanent cure for hypertension in future.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]