A scoping review of neuromodulation techniques for controlling blood pressure: what are the ups and downs to this approach?

A New Era of Renal Denervation Trials for Patients With Hypertension?

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Renal denervation in hypertension patients: Proceedings from an expert consensus roundtable cosponsored by SCAI and NKF.

Usefulness and limitations of saralasin, a partial competitive agonist of angiotensin II, for evaluating the renin and sodium factors in hypertensive patients

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial

The renal nerves contribute to hypertension through effects in the kidney that enhance sodium retention and renin secretion, and by effects in the central nervous system that increase systemic sympathetic activity. Therefore, targeting the renal nerves provides a logical basis for treating hypertension. Several trials of renal denervation––achieved by applying radiofrequency energy through catheters placed in the renal arteries–– have been completed. Clinical results have been inconsistent, however, partly because of factors related to the ablation technique and partly because these studies have been performed in patients with the inadequately defined clinical condition of “treatment-resistant hypertension.” This statement now explains our conclusion that future studies of renal denervation should be guided by the established randomized, controlled clinical trial designs used for studying antihypertensive drugs and other treatments for hypertension. © 2015 Wiley Periodicals, Inc.

See related article, pp 450–456 In 2009, Krum et al1 reported a substantial blood pressure decrease (−27/17 mm Hg at 12 months) after percutaneous radiofrequency catheter-based renal sympathetic denervation in a cohort of 45 patients with resistant hypertension. One year later, the results of this proof-of-concept study were confirmed in 106 resistant hypertensive patients randomized 1:1 to renal denervation plus previous drug treatment versus drug treatment alone, with a blood pressure decrease of −32/12 mm Hg at 6 months in the renal denervation group ( P <0.0001), contrasting with virtually unchanged blood pressure in the control group (SYMPLICITY HTN-2).2 However, the SYMPLICITY studies have important limitations, addressed in detail elsewhere.3 Accordingly, there is a growing consensus that renal denervation should remain the ultima ratio in resistant hypertension3 and should only be administered by multidisciplinary teams in tertiary referral centres, after careful patient selection. Unfortunately, besides higher baseline systolic blood pressure and use of central sympatholytic agents,4 SYMPLICITY studies failed to identify independent predictors of blood pressure response after renal denervation. Therefore, patient selection is almost entirely based on negative criteria, such as exclusion of patients with secondary and white coat hypertension or with narrow or too short renal arteries. In individual cases, whether lack of blood pressure decrease after renal denervation is due to poor contribution of the sympathetic system to the pathogenesis or the maintenance of hypertension, …

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …

Trial: 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, 376:1903–1909. Rating: ••Of major importance. Introduction: Sympathetic overactivity is thought to be a major contributor to the pathogenesis and progression of human hypertension [1, 2]. In particular, renal sympathetic activation results in renal vasoconstriction, increased renin secretion, and enhanced sodium and water reabsorption, all of which contribute to the development of hypertension [3]. Despite this mechanistic understanding, attempts at modulating sympathetic tone with antiadrenergic drug therapy have been limited by their poor clinical performance and undesirable side-effect profile [1, 4]. Additionally, historic surgical approaches for the treatment of hypertension with renal sympathectomy have long been abandoned due to a high perioperative morbidity and mortality [5, 6]. In recent years, the advent of a catheter-based technique using radiofrequency to destroy the renal nerves has revitalized these long abandoned thoughts of treating hypertension with renal denervation. Following encouraging results of an uncontrolled feasibility trial and a case report [7, 8], a recent randomized controlled trial (Symplicity HTN-2 [Renal Denervation in Patients With Uncontrolled Hypertension]) has further demonstrated the potential for catheter-based renal denervation in the treatment of drug-resistant hypertension. Aims: The Symplicity HTN-2 trial was designed to determine the safety and effectiveness of catheter-based renal artery denervation with the Symplicity Catheter System (Ardian, Palo Alto, CA) in reducing blood pressure in patients with drug-resistant hypertension. Methods: In this multicenter trial (involving 24 centers in Europe, Australia, and New Zealand), 106 patients ages 18 to 85 years with a systolic blood pressure of 160 mm Hg or more (≥150 mm Hg in patients with type 2 diabetes), despite treatment with three or more antihypertensive medications were randomized to undergo renal denervation while continuing prior drug therapy or to continue prior drug therapy alone. Patients who met initial screening criteria were subsequently excluded from the trial if their blood pressure fell below eligibility criteria at a second clinic visit after a 2-week screening phase. During this phase, patients were required to document medication compliance and twice-daily home blood pressure monitoring. Patients were also excluded if they were found to have unfavorable renal artery anatomy on imaging; other exclusion criteria included an estimated glomerular filtration rate of less than 45 mL/min/1.73 m2 and type 1 diabetes. The trial’s primary end point was the change from baseline in seated office-based measurement of systolic blood pressure at 6 months. During the intervention, the catheter was advanced into the renal arteries and four to six discrete low-power radiofrequency treatments were applied along the length of both renal arteries. Background use of antihypertensive drugs was held constant for the duration of the trial in both groups. Results: At baseline, the groups were well matched on most characteristics: office blood pressure was 178/96 mm Hg in the intervention group (n = 52) and 178/97 mm Hg in the control group (n = 54). Office-based blood pressure fell by 32/12 mm Hg (SD 23/11; P < 0.001) in the patients who underwent renal denervation versus no change in the control group (1/0 mm Hg, SD 21/10; P = NS). Home blood pressure fell by 20/12 mm Hg (SD 17/11) in the renal denervation group (n = 32) versus no change in the control group (n = 40). Twenty-four-hour ambulatory blood pressure fell by 11/7 mm Hg (SD 15/11; P < 0.006) in the renal denervation group (n = 20) versus no change in the control group (n = 25). There were no serious procedural complications in the denervation group and no between-group differences in renal function or in the incidence of adverse events. Discussion: The authors concluded that renal artery denervation is safe and effective in reducing office blood pressure, home blood pressure, and 24-h blood pressure at 6 months in patients with drug-resistant hypertension.

Blood pressure target goals from guidelines of 2002-2014.

Decreases in blood pressure in response to L-Glutamate microinjections into the A5 catecholamine cell group

Background/Introduction Three recently published sham-controlled studies proved the efficacy of renal denervation (RDN) in hypertensive patients. However, there it is still unclear which patients should be selected for RDN. Purpose This study seeks to clarify which patient subgroups benefit most from radiofrequency RDN by analysing a nationwide multicentre registry database. Methods This is a post-hoc analysis from the multicentre Austrian Transcatheter Renal Denervation Registry hosted by the Austrian Society of Hypertension. We correlated change of systolic blood pressure (BP) after RDN to gender and presence/absence of comorbidities. Bivariate correlation and multiple linear regression analyses were performed. Results 291 patients (43% female, median age 64 years) undergoing RDN between April 2011 and September 2014 were included in this analysis. Mean baseline ambulatory 24-hour BP (systolic/diastolic) was 150±18/89±14 mmHg and mean baseline office BP was 170±16/94±14 mmHg. After RDN, mean ambulatory 24-hour BP reduction was 9±19/6±16 mmHg. The following features were associated with a good response to RDN: high baseline systolic ambulatory BP (ρ=0.53, p&lt;0.001), high baseline diastolic office BP (ρ=0.40, p&lt;0.001), female gender (ρ=0.10, p=0.049), absence of diabetes mellitus (DM, ρ=0.11, p=0.033), and absence of peripheral arterial disease (ρ=0.17, p=0.002). Multivariate analysis identified high baseline systolic ambulatory BP, female gender and absence of DM as independent predictors for systolic ambulatory BP reduction (systolic ambulatory BP: HR 5.83 [95% CI 4.83–6.83], p&lt;0.001; absence of DM: HR 5.82 [2.04–9.60], p=0.003; female gender: HR 5.07 [1.46–8.68], p=0.006), although women and patients without DM had lowest baseline ambulatory BP. Furthermore, both women and patients without DM used significantly less antihypertensives after RDN (female vs male: 4.0±1.3 vs 4.4±1.3, p=0.002; no DM vs DM: 4.0±1.3 vs 4.6±1.3, p&lt;0.001). Figure 1 Discussion Ambulatory BP reductions after RDN were substantially more pronounced in female and in non-diabetic patients despite lower baseline BP. It is concluded that in terms of efficacy female patients and non-diabetics might be more suitable for RDN. Acknowledgement/Funding The Austrian Renal Denervation Registry was funded by the Austrian Society of Hypertension.

Sirs: The underlying mechanisms for the rise in blood pressure in individuals with autosomal dominant polycystic kidney disease (ADPKD) are complex, and experimental and clinical data support the concept that sympathetic hyperactivity may contribute to the pathogenesis of hypertension in ADPKD [1, 2]. More recently, a catheter-based percutaneous aimed at ablating both efferent and afferent renal nerve fibres has been introduced into clinical medicine and has been demonstrated to safely and effectively reduce blood pressure in patients with treatment resistant hypertension and normal renal function [3–6]. However, to our knowledge there is only one report of Shetty et al. [7] who observed after renal denervation resolution of chronic pain related to renal cysts and delayed fall in blood pressure in patient with ADPKD and resistant to treatment hypertension. No data on reduction of sympathetic activity has been shown. A 26-year-old male with polycystic kidney disease was referred to the Department of Hypertension by the end of 2012 for the consideration of percutaneous renal denervation due to resistant hypertension. At the age of 20, the patient was first diagnosed with hypertension and also with ADPKD. A family history of polycystic kidney disease was present in the mother and in addition to in a sister. At the time of referral, the patient had an office blood pressure of 162/77 mmHg and an average day-time ambulatory blood pressure of 138/73 mmHg despite four antihypertensive medications comprising valsartan 160 mg od, amlodipine 10 mg od, nebivolol 2.5 mg od, and hydrochlorothiazide 25 mg od. No history of cardiovascular disease or diabetes was reported, the patient has never smoked. The patient has normal renal function at baseline with a serum creatinine of 74 μmol/L and estimated glomerular filtration rate by MDRD formula of >60 mL/min/1.73 m2. The patient was not troubled by chronic flank pain. On Doppler duplex examination renal arteries were normal, renal resistive index values were 0.61 and 0.66 in the right and left kidney, respectively. Abdominal ultrasound showed enlarged size of right (145 mm) and left (180 mm) kidney with multiple simple renal cortical cysts with a maximum diameter of 3 cm. Hepatic cysts were not present. Abdominal MRI showed bilateral simple appearing renal cysts in the upper and lower poles. Microneurography was performed before and 3 months after the renal denervation. Muscle sympathetic-nerve activity (MSNA) signals were recorded by an electrode placed into the peroneal nerve at the popliteal fossa, posterior to the fibular head and the reference electrode was placed subcutaneously 2–3 cm from the recording electrode. Due to his uncontrollable blood pressure percutaneous renal sympathetic denervation using the Symplicity Catheter® system was performed as described previously [5], with five ablations in left and six in right renal artery (Fig. 1). The patient was discharged the following day on his pre-ablation antihypertensive regimen. The only complication of the procedure was transient stenosis of both arteries resulting from artery spasm and edema. Fig. 1 Symplicity Catheter® in the left renal artery. It was possible to perform five ablations in the left renal artery The patient was reviewed at 1 and 3 months post renal sympathetic denervation. At 1 month follow up he had improvement in his systolic blood pressure with an office reading of 129/60 mmHg and at 3 month follow up his blood pressure had dropped to 120/74 mmHg. A 24-h ambulatory blood pressure monitoring at 1 and 3 months confirmed blood pressure control with a mean day-time blood pressure of 131/68 and 128/65 mmHg, respectively. His renal function remained unchanged at 1 and 3 months. Microneurography at 3 months showed a reduction in MSNA (Fig. 2), as assessed in the peroneal nerve. Fig. 2 Reduction in blood pressure and muscle sympathetic-nerve activity (MSNA), as assessed in the peroneal nerve on microneurography 3 months after bilateral renal-nerves ablation Our case report confirms the safety and effectiveness of a catheter-based renal denervation approach for the treatment of resistant hypertension in patients with ADPKD. While a single case has its obvious limitations, the fall in blood pressure after the procedure was accompanied by the decrease in the sympathetic activity being likely mediated via ablations of different fibres responsible. However, it should be mentioned that MSNA may not give information specifically about renal sympathetic activity [8]. In our case, larger reductions in office than in ambulatory blood pressure were noticed. However, these changes were of comparable magnitude as reported in the prospective studies [5, 9, 10]. In these groups, also the discrepancy between reduction in office and ambulatory blood pressure was also noted, but is should be stressed that observed reductions provide an equivalent reduction in cardiovascular events [5, 8, 11]. Confirmation of substantial BP lowering via catheter-based renal afferent denervation in patients with ADPKD in future studies may provide a valuable and safe alternative for the management of this difficult clinical condition.

Neurotensin administered intravenously in a dose of 1 nmole/kg produced triphasic blood pressure responses in anesthetized rats: the first depressor, second pressor and third depressor responses. The first depressor response was significantly suppressed by treatment of animals with a mixture of diphenhydramine and metiamide or chronic administration of compound 48/80, but was not modified by treatment with atropine, phentolamine, yohimbine, propranolol, sulpiride and adrenalectomy. The second pressor response was abolished by phentolamine, yohimbine and adrenalectomy. The second phase response was also markedly reduced by diphenhydramine in reserpinized rats and chronic administration of compound 48/80. The third depressor response was blocked by treatment of animals with diphenhydramine or chronic administration of compound 48/80. These results suggest that neurotensin may produce an immediate depressor response (the first phase) partly through a histamine-mediated process, and the second pressor response is produced by catecholamines released from the adrenal medulla through a histamine-mediated process. The third depressor response appears to be mediated mainly by histamine. The participation of mast cells as an origin of histamine which mediates these processes is suggested.

the cumulative sodium retention. Furthermore, this renal denervation was shown to prevent, markedly attenuate or delay the development of hypertension in a diverse number of models of elevated blood pressure. 4 These promising experimental results of renal sympathetic nerve denervation for the treatment of hypertension prompted the establishment of the first clinical trial of this approach as a proof-of-principle study. 3 In brief, in 45 patients with resistant hypertension a catheter connected to a radiofrequency generator was introduced into renal arteries via femoral access and up to six discrete radiofrequency ablations were delivered within each renal artery. The major aims of this study were to assess firstly the efficacy of blood pressure lowering and s econdly the safety of this procedure. The initial blood pressure in these patients who had been treated with four to seven anti-hypertensive medications was 177/101 mmHg. The highly significant average reduction in office measured systolic/diastolic blood pressure at 1 month after the renal sympathetic denervation procedure was 14/10 mmHg. Blood pressure was further reduced at 3 months by 22/10 mmHg, with this effect persisting on s ubsequent assessments with the reduction 12 months after the procedure being 27/17 mmHg. Only six out of 45 patients did not benefit from this treatment, defined as a s ystolic blood pressure reduction of less than 10 mmHg. In 12 patients, 24 hour ambulatory blood pressure monitoring was performed before and after the denervation procedure. The change in office systolic blood pressure correlated closely with the change in mean ambulatory blood pressure (r 2 50.62, p50.002). Furthermore, renal sympathetic denervation was associated with an increase in the number of n octurnal dippers in the group of patients that had responded to this treatment. The effectiveness of the radiofrequency method in achieving efferent renal denervation was assessed in a subgroup of patients (n 51 0) by measuring renal Arterial hypertension is a major risk factor for an array of cardiovascular diseases, particularly in the context of concomitant diabetes. Furthermore, elevated blood pressure is at least twice as prevalent in type 2 diabetes as in the g eneral population. Clinical data suggest that lower blood pressure may induce even greater cardiovascular benefits in diabetic subjects than in individuals without diabetes. With respect to renal disease, recent data from the Action in Diabetes and Vascular Disease (ADVANCE) study indicate that there is no lower threshold for blood pressure reduction when one is aiming to reduce the burden of renal disease. 1 So far, the major therapeutic strategy for arterial hypertension has focused on pharmacological treatments. Despite the abundance of available antihypertensive drugs, arterial hypertension remains undertreated, in particular in diabetes and specifically in the setting of associated chronic kidney disease. Clinical trials involving patients with diabetes or renal impairment have demonstrated that achieving lower blood pressure goals requires treatment with on average at least three different antihypertensive agents. 2 Moreover, it has been shown that with current standard antihypertensive therapies only one of out seven patients with type 2 diabetes can achieve a target blood pressure of less than 130/80 mmHg. Recently, a multi-centre prospective cohort study has demonstrated the efficacy of a non-pharmacological, minimally invasive percutaneous radiofrequency catheter-based treatment to disrupt renal sympathetic nerves in the management of patients with resistant hypertension, which included a significant subgroup with type 2 diabetes. 3 The rationale for renal sympathetic nerves denervation as a treatment strategy for systemic hypertension lies in the hypothesis that abnormal excretory function is crucial for the initiation, p rogression and maintenance of primary hypertension with sodium and water balance considered to be of central importance in the long-term control of systemic blood pressure. In addition, in animal models it has been confirmed that renal sympathetic nerve stimulation results in a substantial increase in the renin secretion rate and promotes antinatriuresis without affecting glomerular filtration rate and renal plasma flow. Moreover, in animal models renal sympathetic denervation has been used to demonstrate that renal sympathetic nerve activity is responsible for approximately 40% of