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Device-Based Treatment in Hypertension: At the Forefront of Renal Denervation

Kario, Kazuomi1,∗; Hettrick, Douglas A.2; Esler, Murray D.3

Editor(s): Fu, Xiaoxia; Xu., Tianyu

Author Information
doi: 10.1097/CD9.0000000000000018
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Abstract

Introduction

Hypertension is the most powerful risk factor for cardiovascular diseases, yet despite a national prevalence of nearly 50%, the control rate in Japan is only slightly above 30%.[1] Device-based therapies have recently received much attention as an additional treatment option besides drugs for poorly controlled hypertension.[2,3] They include renal denervation (RDN), which involves transcatheter denervation of the renal sympathetic nerve and baroreflex activation therapy, which involves electrical stimulation of one carotid artery baroreceptor. These device-based therapies are also known as neuromodulation therapies because they suppress the sympathetic nervous system and modify neurohumoral regulatory mechanisms.[3] These treatments have been shown to significantly lower blood pressure (BP) in clinical trials, but of these, the one closest to clinical application for hypertension is RDN.

This article focuses on RDN and summarizes the latest results of clinical trials, its antihypertensive mechanism, and how it can be incorporated into future hypertension and cardiovascular treatment strategies.

History [Figure 1]

Already prior to and during the 1950s, surgical sympathectomy was being performed on hypertensive patients. Although its antihypertensive effect was recognized, the procedure was not clinically widespread due to side effects such as perioperative complications and postoperative postural hypotension.[4]

F1
Figure 1:
Clinical trial history of RDN. BP: Blood pressure; RDN: Renal denervation.

In 2009, the first hypothesis-testing SYMPLICITY HTN-1 trial (HTN-1) reported a remarkable antihypertensive effect in drug-resistant hypertension using minimally invasive radiofrequency transcatheter RDN.[5] In this study, 153 patients with drug-resistant hypertension and prescribed 3 or more antihypertensive medications, including diuretics, showed a decrease in office BP of −27 mmHg systolic and −17 mmHg diastolic at 12 months of follow-up after RDN and then significant and sustained reductions in BP were shown over 36 months.[5]

The subsequent SYMPLICITY HTN-2 (HTN-2) trial, published in 2010, included 106 patients with treatment-resistant hypertension randomized to pharmacotherapy plus RDN (52 patients) or conventional pharmacotherapy (54 patients). Systolic BP (SBP) decreased significantly compared to the conventional therapy group at 6 months and favored RDN by −33/−11 mmHg. The differences in both SBP and diastolic BP (DBP) were statistically significant and the reductions of observed BP were maintained to the final follow-up at 36 months.[6] Twenty-four-hour mean BP also decreased significantly in a subgroup of patients, although the magnitude of the reduction was lower than that of office BP with a between-group difference of about −8/−6 mmHg at 6 months.

The results of HTN-1 and HTN-2 were cited in the 2013 ESH/ESC Guidelines for the management of arterial hypertension,[7] which made RDN a Class I indication for treatment-resistant hypertension, and led to the initiation of the SYMPLICITY HTN-J study in Japan. RDN was performed for the first time in Japan in a treatment-resistant hypertensive population using the first generation, single electrode radiofrequency (RF) Symplicity “Flex” catheter (Medtronic) and found to be highly effective upon initial investigation [Figure 2]. However, in 2014, the SYMPLICITY HTN-3 (HTN-3) trial with a sham-controlled comparison group that included renal arteriography but not RDN reported no significant difference in BP lowering level between the RDN and sham group.[8] These surprising results of HTN-3 led to post hoc identification of several trial elements that may have confounded the results including lack of procedural experience among trial investigators and especially apparent changes in patient antihypertensive drug adherence behavior as indicated by large 6-month reductions in office BP in the sham control group.[9]

F2
Figure 2:
ABPM of the first renal denervation case in Japan. Male, 38 years old, hypertension and diabetes mellitus (taking CCB, ARB, Thiazide, β-blocker). ABPM: Ambulatory blood pressure monitoring; ARB: Angiotensin II receptor blocker; BP: Blood pressure; CCB: Calcium channel blocker; RDN: Renal denervation.

In the aftermath of HTN-3, several RDN trials were stopped. In addition, all RDN clinical trials that aimed to obtain national insurance coverage were subsequently disallowed unless the sham group was included. Thus, the HTN-J trial, already underway in Japan, was canceled midway through the enrollment period. However, a subsequent pooled analysis combining data from both the HTN-3 trial and interim analysis data of HTN-J found that RDN clearly lowered the BP during the nighttime and early morning, when the effect of the antihypertensive drug changes are less likely to be seen [Figure 3].[10] In fact, in HTN-3,[9] about 40% of patients in both the RDN and sham groups changed their antihypertensive medications during follow-up. Likewise, in 2015, the French prospective randomized DENERHTN trial reported positive results using similar techniques and the same device as the SYMPLICITY HTN trial series.[11] The trial compares RDN (n = 53) to standardized stepped-care antihypertensive treatment (n = 53) in resistant hypertensive patients and showed significant between-group reductions in the primary endpoint of daytime SBP (−5.9 mmHg, P = 0.0329) at 6 months. This trial also reported high levels of drug nonadherence of about 50% at 6 months but the levels were similar between groups.[12]

F3
Figure 3:
Six-month change in systolic blood pressure stratified by morning, night, and daytime. Pooled analysis (HTN-J and HTN-3).[10] BP: Blood pressure; RDN: Renal denervation.

Learning from the failure of the HTN-3 trial, a new clinical trial program named SPYRAL HTN was initiated with an improved design to compensate for confounding factors associated with HTN-3.[9,13] The protocol modification was especially focused on patient selection, procedural details, and variability in patient drug nonadherence behavior. A second-generation multi-electrode device catheter (Symplicity Spyral, Medtronic) capable of ablating four-points simultaneously in a helical pattern was applied and therapy was extended to distal areas of the renal artery beyond the main bifurcation where the renal sympathetic nerves converge. In addition, to minimize procedural variability, the facilities and operators were limited to centers with extensive prior experience.

The primary endpoint was changed in the SPYRAL HTN trials from highly variable office BP to the decrease in 24-hour mean SBP, measured by ambulatory BP monitoring (ABPM). ABPM has less day-to-day variability and is more strongly associated with cardiovascular risk.[14,15] Patients with office SBP 150 to 179 mmHg and a mean 24-hour ambulatory SBP 140 to 169 mmHg were included, while DBP ≥ 90 mmHg were also added as one of the inclusion criteria to exclude structural hypertension with advanced vascular stiffness.

In 2017 to 2018, the results of the SPYRAL HTN (OFF-MED and ON-MED) feasibility studies were published respectively, and both showed impressive results with significant intergroup differences in both office and ambulatory SBP and DBP.[16,17] In 2018, BP reduction was also observed with a significant difference compared to the sham procedure group in different denervation systems using ultrasound.[18] In 2020, the prospectively powered SPYRAL HTN OFF-MED pivotal trial also showed positive results, and thus finally the possibility of introducing transcatheter RDN into clinical practice is on the horizon.[19]

Evidence for treating hypertension

SPYRAL trials

The SPYRAL HTN OFF-MED and ON-MED trials are multicenter international feasibility studies conducted in Europe, the United States, Australia and Japan, using the second generation Spyral radiofrequency ablation system.[16,17]

In 2017, the SPYRAL HTN OFF-MED trial, which was conducted in hypertensive patients who did not take antihypertensive medication, demonstrated significant reductions in the RDN group (n = 38) as corrected for sham (n = 42) in 24-hour SBP at 3 months of −5.0 mmHg [Figure 4]. In 2018, the results of the SPYRAL HTN ON-MED trial, which enrolled patients taking 1 to 3 antihypertensive drugs in a similar protocol, were published.[17] In this study, 24-hour SBP was significantly lowered by −7.4 mmHg in the RDN group (38 patients) compared to the sham group (42 patients) after 6 months of observation [Figure 4]. In 2020, results of the SPYRAL HTN-OFF MED pivotal study were released. Based on Bayesian theory, this pivotal study included patients from the OFF-MED feasibility study and continued the same protocol, expanding the number of patients to 331. Meanwhile, in the aforementioned studies, the RDN group also showed a sham-corrected decrease in 24-hour SBP and office SBP of −4.0 and −6.6 mmHg, respectively, compared to the sham group at 3 months from baseline [Figure 5].[19] These sham-controlled studies proved that RDN lowers BP in hypertensive patients. In 2021, results of the prospectively powered sham controlled SPYRAL HTN-ON MED extension are expected to be released.[20]

F4
Figure 4:
Twenty four-hour Systolic blood pressure changes derived from four recent prospective randomized controlled trials.[16–18,25] RDN: Renal denervation.
F5
Figure 5:
SPYRAL OFF-MED Pivotal trial. Changes in 24-hour and office systolic and diastolic blood pressure (BP).[19] DBP: Diastolic BP; SBP: Systolic BP.

RADIANCE- HTN SOLO study

RADIANCE-HTN SOLO was a multicenter, international, single-blind, randomized, sham-controlled trial using the Paradise (Recor Medical) balloon-tipped ultrasonic denervation catheter system in untreated hypertensive patients. The RDN group had a greater reduction in the primary endpoint, that is, daytime ambulatory SBP at 2 months, than in the sham group (between-group difference of −6.3 mmHg) [Figure 4]. This study demonstrated that transcatheter RDN can achieve a similar degree of BP reduction by using a completely different technique. A unique feature of this study was the availability of antihypertensive medication after 2 months of randomization. After 6 months, the number of antihypertensive drugs per patient was significantly lower in the RDN group (0.9 ± 0.9 vs. 1.3 ± 0.9 in the sham group, P = 0.010). Additionally, awake SBP measured by ABPM was significantly lower in the RDN group than in the sham group (difference adjusted for baseline BP and number of medications: −4.3 mmHg).[21] These results suggest that RDN may reduce the number of subsequent doses of antihypertensive medication, thereby attenuating the impact of poor drug adherence and the need for polypharmacy.

Evidence from the Japanese population

Asians are known to be relatively salt-sensitive compared to other racial groups, and they are also known to consume more salt than Westerners.[22,23] Asians have higher rates of strokes and heart failure, are at greater risk than Westerners for BP dependence, and the benefit of RDN may be greater.[24]

The Symplicity HTN-J trial for treatment-resistant hypertension in Japan was initiated with a target enrollment of 100 patients but was discontinued after the inclusion of only 41 patients following the unexpected neutral results of SYMPLICITY HTN-3. However, the reported absolute value of 24-hour SBP by RDN is comparable to 3 recent trials with sham comparison, including nighttime and early morning BP [Figure 4].[25] This indicates that the main renal artery ablation alone can significantly lower BP. In addition, long-term results of HTN-J showed that the antihypertensive effect was maintained over a 3-year period, with sustained systolic office BP reductions greater than −30 mmHg at 36 months [Figure 6].[26]

F6
Figure 6:
Sufficient and persistent blood pressure reduction in the long-term results from SYMPLICITY HTN-Japan. RDN arm and crossover arm.[26] BP: Blood pressure; DBP: Diastolic BP; RDN: Renal denervation; SBP: Systolic BP.

Further evidence of the benefit of RDN in the Asian population has been reported in a long-term registry-based analysis, showed that the antihypertensive effect of RDN in a Korean population was superior to that of a matched Western cohort.[27] Recently, the Asian RDN Consortium of RDN experts published a consensus on RDN, based on the latest clinical data. In addition to HTN-J in Japan, data from other Asia regions suggest that RDN is effective in treating nocturnal and early morning hypertension, which is common in Asia, and RDN is likely to lower the BP of poorly controlled hypertensives, including patients with treatment-resistant hypertension, over the long term.[28] Currently, clinical trials are being conducted in Japan by Japan Medtronic (SPYRAL denervation system), JIMRO of the Otsuka Holdings Group (Paradise denervation system), and Terumo (IBERIS denervation system, radio wave) [Table 1].[29]

Table 1 - Ongoing renal denervation trials in Japan
Product (company) Technology Proof of concept trials Pivotal trials (sham controlled)
Paradise (ReCor) Ultrasound RADIANCE Trio (US/EU)RADIANCE Solo (US/EU) REQUIRE (JP/KR)RADIANCE (US/EU)
Spyral (Medtronic) Radiofrequency SPYRAL HTN ON-MED (US/EU/JP/AUS)SPYRAL HTN OFF-MED (US/EU/JP/AUS) SPYRAL HTN ON-MED (US/EU/JP/AUS)SPYRAL HTN OFF-MED (US/EU/AUS)
Iberis (Terumo/AngioCare) Radiofrequency IBERIS (JP) NA
AUS: Australia; EU: Europe; JP: Japan; KR: Korea; NA: No sham arm in Iberis trial; US: United State. Source: clinicaltrials.gov (https://www.clinicaltrials.gov/); umin clinical trials registry (https://www.umin.ac.jp/english/).

The global SYMPLICITY registry (GSR)

The ongoing prospective GSR is an international registry of sympathetic RDN in poorly controlled hypertension patients. In the most recent update, the registry included 2747 patients and the overall reduction in 24-hour SBP at 3 years was −9.2 mmHg.[30] In addition, similar significant reductions in 24-hour BP were reported in several high-risk patient sub-groups including −10.4 mmHg in patients with treatment-resistant hypertension, −8.7 mmHg in the elderly over 65 years of age, −10.2 mmHg in diabetics, −8.6 mmHg in patients with isolated systolic hypertension, −10.1 mmHg in patients with chronic kidney disease (CKD), and −10.0 mmHg in patients with atrial fibrillation (P < 0.0001 for all).[31] Besides these specific co-morbid subgroups, the antihypertensive effect of RDN was also shown to be unaffected by the subgroup of patients with higher atherosclerotic cardiovascular disease risk scores.

Safety of the RDN procedure

Short- and long-term analyses from clinical trials and registries, as well as several recent meta-analyses,[32–35] support the safety of the RDN procedure, particularly with more frequently studied radiofrequency devices. No patients in the SPYRAL HTN ON- and OFF-MED trials[16,17] and 1 patient in the RADIANCE HTN SOLO trial[18] received a renal artery stent following the RDN procedure over 3 to 6 months of follow up. Likewise, a recent meta-analysis of 50 published trials, including 5769 subjects with 10,249 patient-years of follow-up, reported a pooled annual incidence rate of 0.20% of stent implantation following radiofrequency RDN (95% CI: 0.12%–0.29% per year).[35] Sub analysis of the Global SYMPLICITY Registry showed a modest decline in renal function through 3 years of follow up in patients without CKD defined as baseline eGFR ≥60 mL/(min·1.73 m2) (−7.1 mL/(min·1.73 m2)) as well as in patients with CKD (−3.7 mL/(min·1.73 m2)).[36] Recent meta-analyses also determined minimal change in renal function following RDN in single-armed trials[32] and comparison to untreated control groups.[33,34]

Other diseases that may benefit from RDN

RDN is expected to directly ameliorate not only hypertension, but also various diseases related to increased sympathetic nerve activity. For example, RDN has been reported to improve conditions such as atrial fibrillation,[37–40] heart failure, ventricular tachycardia,[41,42] as well as sleep apnea,[43] diabetes mellitus,[44,45] and CKD.[46–50] It is known that the autonomic nervous system is intricately involved in the development and persistence of arrhythmias and several reports have indicated that RDN is effective for both atrial and ventricular arrhythmias. In atrial fibrillation, results of randomized controlled trials have recently been published. In the ERADICATE study, 302 patients with paroxysmal atrial fibrillation and prescribed antihypertensive therapy were randomized into 2 groups including pulmonary vein isolation plus RDN and pulmonary vein isolation alone. The primary endpoint of freedom from atrial fibrillation, atrial flutter, or atrial tachycardia at 12 months was attained by 57% in the pulmonary vein isolation alone group and 72% in the pulmonary vein isolation plus additional RDN group, indicating a significant benefit of RDN (hazard ratio 0.57, P = 0.006).[37] The difference in BP reduction between the 2 groups was −13 mmHg in favor of the RDN group. Left ventricular hypertrophy and left atrial enlargement are themselves risk factors for the development of atrial fibrillation, but RDN has been reported to improve them[19,51–54] and a randomized sham-controlled trial using cardiac MRI showed that the stroke volume index was reduced by 4.7 mL/m2 in the RDN group (difference between the 2 groups P = 0.008).[55] Furthermore, RDN has significantly improved the 6-minute walk in patients with chronic heart failure.[56]

Advances in devices

Several RDN devices have been introduced clinically, and to date serious complications directly related to the procedure are rare [Figure 7].[57]

F7
Figure 7:
Various designs and energy sources for catheter based RDN systems. (A) Multi-electrode radiofrequency spiral design (Symplicity Spyral, Medtronic). (B) Irrigated balloon ultrasound (Paradise, ReCor). (C) EtOH injection (Peregrine, Ablative Solutions). RDN: Renal denervation.

Symplicity Spyral system (radiofrequency thermal ablation)

The first-generation radiofrequency SYMPLICITY “Flex” ablation device used in the SYMPLICITTY HTN trial series had only 1 electrode, and required rotation and repositioning between lesions, resulting in between-operator variability. The subsequent SPYRAL HTN studies employed a second-generation spiral-shaped catheter device (Symplicity “Spyral”). This device allows simultaneous independent ablation and temperature and impedance monitoring at 4 radially and longitudinally dispersed positions, ensuring electrode-tissue contact and reducing the risk of stenosis.

Anatomically, the renal sympathetic nerves diverge from the aorta and course away from the renal artery near the aorta, but converge at the distal end where the main artery enters the kidney. Therefore, more complete denervation can be achieved by performing ablations in the distal portion of the main renal artery and in the branching vessels. Animal studies have also demonstrated that performing ablations in the branch vessels, as well as the main artery, is more effective in reducing renal norepinephrine levels than performing ablations only in the main artery.[58,59]

In the SPYRAL HTN OFF MED/ON MED study, ablations were performed in both the main renal arteries and vessel branches by using Spyral catheter. This important procedural modification that resulted from human anatomical data showing that many late-arriving renal nerves converge with the artery distal to the main bifurcation.[60,61] These anatomical data were further supported by pre-clinical data showing greater reductions in real norepinephrine[58] and clinical trials showing an association between incrementally greater BP reductions with distal and branch ablation compared to main artery ablation only.[62,63]

Paradise system (ultrasonic thermal ablation)

In the RADIANCE-HTN SOLO study, the Paradise system (ReCor) was used to perform RDN by ultrasound emissions in patients not taking any anti-hypertensive medications. The Paradise device cools the renal arterial walls via a circulating fluid-filled balloon while delivering ultrasonic energy circumferentially, allowing ablation of the sympathetic nerves. Multiple sequential ablations are typically performed in the main vessel. The ongoing, international, prospective, randomized sham-controlled RADIANCE HTN-TRIO trial will further evaluate the efficacy of RDN in patients with uncontrolled hypertension despite treatment with antihypertensive medication.

Peregrine system (trans-arterial alcohol injection)

Recently, a multicenter, open-label first-in-man study tested the efficacy and safety of the Peregrine catheter system (Ablative Solutions) that chemically denervates the sympathetic nervous system by injecting dehydrated alcohol locally into periadventitial space of the renal artery.[64] Forty-five treatment-resistant hypertensive patients received 0.6 mL of alcohol injection in each renal artery. After 6 months, 24-hour SBP was reduced by −11 mmHg and DBP by −7 mmHg. No significant complications occurred, with transient microleaks observed in 42% and 49% of the left and right renal arteries, respectively, and small dissections in 2 cases, which did not require subsequent treatment. Prospective randomized sham-controlled trial of this system is ongoing.

Other energy modalities

Various other modalities, including microwave,[65] ionizing radiation,[66] cryo-ablation[67,68] and modified laparoscopic techniques[69,70] have been studied for RDN application, each with specific potential clinical advantages. However, these technologies have not yet progressed beyond the pre-clinical or early first in man phase of research. They will require rigorous prospective clinical evaluation to determine respective safety and efficacy compared to established modalities such as radiofrequency.

Procedural endpoints

Unlike most interventional cardiology procedures, no reliable clinical endpoint has yet been established to indicate complete nerve destruction. Hence, most procedures are performed according to clinical trials or manufacturer recommendations to completely treat the vessel. However, some novel techniques have shown promise to indicate procedural success. For example, short-duration radiofrequency stimulation of the renal artery results in a renal afferent nerve-mediated transient increase in arterial BP, whereas the amplitude of the BP elevation appears to decrease after effective RDN. Thus, renal artery stimulation might be adequate to predict BP outcome after RDN.[71] Indeed, a recent study demonstrated that the greater the difference in before and after BP response, the greater the fall in 24 hours BP after 6 months of RDN.[72] Likewise, stimulation of the aorticorenal ganglion from within either the aorta or inferior vena cava increased arterial BP and renal arterial vasoconstriction in an ovine model. The disappearance of these responses could be an endpoint for denervation procedures.[73]

An alternative method to potentially identify adequate efferent nerve destruction via sympathetically-mediated renovascular vasomotion has also been reported recently.[74] Observable changes in low frequency power spectral components derived from real time renal arterial pressure and flow waveforms following sympathetic blockade were reported in both normotensive rabbit and porcine pre-clinical models.

The potential for meta-iodobenzylguanidine (123I-mIBG) scintigraphy imaging, previously applied to detect changes in cardiac sympathetic activity, has also been studied to detect changes in renal sympathetic activity following RDN.[75] Prospective clinical trials will be required to verify these intriguing techniques.

Twenty-four-hour BP lowering and mechanisms of cardiovascular protection

RDN has been shown to lower BP compared to sham control in both the presence and absence of concomitant drug therapy. Thus, RDN-induced BP reductions are not affected by drug adherence, which is a primary weakness of medication therapy.[76,77] This allows for 24-hour BP control, including at night and early in the morning when the antihypertensive effect of the medication is likely to wear off due to the time course of drug ingestion[78] and pharmacokinetics.[2] Initially, it was thought that the SYMPLICITY HTN-3 trial failed to prove the antihypertensive effect of RDN. However, an analysis focused on BP levels at night and early morning actually showed significant BP reductions in the RDN group as compared to sham control.[10] The effects of RDN on 24-hour BP profiles obtained from the SPYRAL HTN OFF MED[19,79] and ON MED[17] studies, the SYMPLICITY HTN-Japan study[25] and the RADIANCE HTN SOLO study[18] are shown in Figure 8.[80] Each study shows that RDN can adequately reduce not only daytime BP but also nocturnal and early morning BP, which are “blind spots” for drug therapy. Therefore, RDN could be a complementary treatment for poorly controlled hypertensive patients with drug therapy, especially during the high-risk nighttime and morning surge periods.

F8
Figure 8:
Twenty-four-hour blood pressure changes derived from 4 recent prospective randomized controlled trials at baseline and follow-up.[80] Data are adapted from: (A, B) the Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications (SPYRAL HTN-OFF MED)[19,79] (3-month follow-up); (C, D) SPYRAL HTN-ON MED[17] (6-month follow-up); (E, F) SYMPLICITY HTN-Japan[25] (6-month follow-up); (G, H) and Study of the ReCor Medical Paradise System in Clinical Hypertension[18] (2-month follow-up). RDN: Renal denervation.

The antihypertensive mechanism of RDN has two major mechanistic pathways [Figure 9].[81] The renal sympathetic nervous system has a centrifugal and sensory afferent pathway, and RDN interferes with both pathways.

F9
Figure 9:
Renal sympathetic nerve anatomy and activity.[81]

The centrifugal pathway runs from the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla of the brainstem through the intermediolateral cell column of the lateral column of the spinal cord and the paravertebral and prevertebral ganglia, and finally through the renal cortex where input modulates renin secretion, sodium reabsorption, and renal vascular resistance. Activation of these sympathetic centrifugal induces antidiuretic effects and increases BP. Likewise, the key nociceptive afferents originate in the renal parenchyma and project to the central nervous system via the dorsal root ganglion in the dorsal root and the dorsal horn of the spinal cord.[82] These afferent nerves sense pressure and osmosis in the renal pelvis and ischemia and pain in the kidney (eg, renal calculi). The 24-hour antihypertensive mechanism of RDN includes denervation of the centrifugal tract, which decreases renin secretion and increases renal blood flow by dilating the renal vessels. Increased sodium excretion decreases circulating blood volume and predominantly lowers nocturnal BP. Denervation of the afferent pathway may also suppress central sympathetic activity and improves baroreceptor sensitivity, thereby reducing excessive BP surges. Therefore, RDN could achieve a 24-hour BP reduction from nocturnal basal BP to early morning surge BP (Hypothesis of perfect 24-hour BP control by RDN) [Figure 10].[2,83]

F10
Figure 10:
Potential mechanisms for the effects of RDN on 24-hour diurnal BP variation.[2,83] BP: Blood pressure; RDN: Renal denervation.

Furthermore, an interesting mechanism has been demonstrated in improving heart failure in animal studies. A study that examined natriuretic peptide metabolism in Spontaneously hypertensive rats and normotensive Wistar-Kyoto rats, creating heart failure by coronary artery ligation, confirmed that RDN suppressed neprilysin activity, increased natriuretic peptides, inhibited myocardial fibrosis, and improved vascular function.[84] It has also been suggested that glucose metabolism may be improved following RDN. Chemical denervation of neurogenic hypertensive Schlager (BPH/2J) mice lowered BP, improved glucose metabolism, decreased expression of SGLT2 protein in the kidneys, and even suppressed endothelial dysfunction.[85] RDN has also been shown to improve glucose metabolism and insulin sensitivity in a cohort of resistant hypertension patients.[44] These results suggest that RDN works to improve glucose metabolism and results in cardiovascular protection. RDN also increased the natriuresis of GLP1Glucagon-like peptide-1 (GLP-1) in a rat model of heart failure.[86] Therefore, further investigation of the interaction of RDN with novel diabetic agents, such as GLP1 agonists and SGLT2 inhibitors, in patients with heart failure and diabetes mellitus is warranted.

Responders and clinical indications

The reported antihypertensive effect of RDN varies between individuals, with apparent responders and non-responders.[10,16–18] There are 3 possible reasons for this uneven antihypertensive effect of RDN. The first is the individual's hypertensive pathology, that is, the extent to which the sympathetic nervous system contributes to elevated BP; the second is the individual's anatomy, that is, the extent to which the person's left and right sympathetic nerve fibers course away from the renal artery[59,60]; and the third is a matter of the operators’ technique, that is, whether he or she was able to accurately denervate the patient. Identification of the best candidates for RDN is important due to the invasive nature of the procedure, although most randomized trials have been prospectively designed to identify responders. Indeed, identification of individual responders may be fraught due to visit-to-visit BP variability.[87]

Initially, the indication for RDN focused on so called “drug-resistant hypertension”, in which BP is not controlled despite prescription of three or more antihypertensive drugs, including diuretics.[5,6] However, 3 recent clinical trials have shown significant antihypertensive effects of RDN in untreated hypertensive patients and in patients taking 1 or 2 antihypertensive drugs.[16–19] The inclusion criteria for clinical trials of RDN have been defined by the level of BP control and by the number of antihypertensive drugs used. Based on the etiology of hypertension, it would be desirable to enroll patients with increased sympathetic nerve activity [Figure 11]. However, no clinical trials have been conducted to date involving such patients [Figure 11].

F11
Figure 11:
Possible indications for renal denervation. BP: Blood pressure; HTN: Hypertension.

A recent post hoc analysis of the SPYRAL HTN OFF-MED trial suggested that RDN provides greater antihypertensive benefits in hypertensive patients with an increased heart rate measured by ABPM.[88] Likewise, sleep apnea syndrome is characterized by nocturnal hypertension with nocturnal BP surge, which is called “neurogenic hypertension” because the sympathetic nervous system activity is increased due to hypoxemia and arousal caused by sleep apnea. RDN suppresses the nocturnal surge of sleep apnea and significantly reduces nocturnal BP [Figure 12].[89,90] RDN has been shown to lower BP and improve apnea/hypopnea index in a randomized trial.[43] Additionally, patients with increased arterial stiffness as indicated by increased pulse wave velocity may not be responsive to RDN,[91] as some post hoc analyses indicated that isolated systolic hypertensive patients with high SBP and DBP below 90 mmHg experienced less BP reduction following RDN. However, a recent analysis of the Global SYMPLICITY Registry showed that, with appropriate adjustments to baseline BP, isolated systolic hypertensive patients experienced similar BP drops. This could indicate that isolated systolic hypertension itself is not a sensitive predictor of increased arterial stiffness.[30,92–94] Thus, RDN may have a greater antihypertensive effect in younger hypertensive patients without developed vascular damage than in elderly hypertensive patients with increased vascular stiffness.

F12
Figure 12:
Impact of RDN on patients with obstructive sleep apnea and resistant hypertension (HTN-3). RDN: Renal denervation.[89,90]

Currently, the most certain clinical indication for RDN is hypertension that cannot be controlled by three or more drugs, including diuretics. As the evidence to date indicates, RDN may be one treatment option for poorly controlled hypertensive patients taking 1 or 2 antihypertensive drugs in the future. Circumstances such as the patient's inability or preference not to use antihypertensive medications due to adverse effects should also be considered. The need for more intensive 24-hour antihypertensive and sympathetic suppression in high-risk groups may require consideration of RDN, depending on comorbidities and risk factors.[31] Indeed, patient's preferences should be taken into account when deciding whether to receive drug treatment or RDN after excluding secondary hypertension in patients with poorly controlled hypertension and confirming that they have “true poorly controlled hypertension” by 24-hour ABPM and are at high risk.

Recent scientific surveys of patients’ preference for RDN relative to additional pharmacologic therapies indicate that roughly 30% to 40% of patients would prefer the option of a one-time invasive procedure as an alternative to increased polypharmacy.[95,96] Also, patient considerations for device therapy contrasted with primary physician concerns that were related to hypertension severity and overall cardiovascular risk.

Japanese hypertensive patients are more likely to have increased early morning BP and morning surge as compared to Blacks and Whites. In addition, Asians are at least twice as sensitive to beta-blockers than Whites.[97] This suggests that Asians may be more sensitive to sympathetic fluctuations, that is, they may be more responsive to RDN.[50] Based on previous clinical studies and reports, the Asia RDN Consortium has recommended that RDN should be considered not only in patients with treatment-resistant hypertension but also in patients with masked hypertension, poorly controlled early morning and nocturnal hypertension, stroke, coronary artery disease, poorly controlled hypertension with a history of heart failure, poor adherence to antihypertensive medication and a 24-hour heart rate >74 beats/min, etc [Figure 13].[50]

F13
Figure 13:
Summary of ARDeC Consensus Panel Recommendations.[50]

Unsolved issues in the treatment of hypertension and expectations for renal denervation

Hypertension is the greatest risk factor for cardiovascular disease, including stroke, myocardial infarction, and heart failure. Strict management of BP throughout 24 hours is therefore recommended from the early stages of the disease.[98,99] Despite the clinical availability of many antihypertensive drugs, the BP control rate in real world is inadequate, with only about one-third of patients reaching the target BP level.[100] Many patients with hypertension still develop cardiovascular diseases at high frequency. The phenomenon whereby hypertension patients suffer debilitating damage despite the existence of effective therapies has been termed the “hypertension paradox”.[80]

Drug therapy alone is insufficient to lower BP globally for 2 main reasons. The first is poor medication adherence. A study conducted in drug-resistant hypertension patients whose adherence to prescribed drug therapy was measured by urine or blood analysis revealed that only about 50% of patients were compliant with their medication. Another weakness of medical treatment includes the difficulty of controlling nighttime BP and the morning surge of BP. The efficacy of drugs tends to be attenuated during the night and early morning and the antihypertensive effect becomes inadequate. Even if the office BP is well controlled, poorly controlled early morning and nocturnal hypertension, plus increased BP variability, increases the risk of cardiovascular diseases.[101–102] On the other hand, the BP lowering effect provided by RDN lasts for at least 3 years with a single treatment and such an effect continues throughout 24-hour includes nights and early mornings.

Thus, RDN is expected to reduce further cardiovascular events by achieving perfect 24-hour BP control, which has not been achieved with medication alone.

Summary

The BP lowering effect of RDN persists over 24-hours including nighttime and early morning. By modifying the sympathetic nervous system which connects the brain and organs, it is expected to have an effect, not only on high BP, but also on the suppression of cardiovascular disease events and organ damage. Some issues remain, such as the identification of responder and the determination of procedural endpoints and clinical outcomes. In the future, translational and clinical research will be vigorously conducted to address these issues and device therapies will establish a position in comprehensive treatment for cardiovascular diseases.

Funding

Dr. Esler has received research support and speaker fees, and has served on the scientific advisory board for Medtronic. Dr. Kario has received research/consultant fees from Medtronic and Omron Healthcare. Dr. Hettrick is a full-time employee of Medtronic.

Conflicts of interest

None.

Editor note: Kazuomi Kario is a member of the editorial board of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.

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Keywords:

Hypertension; Renal denervation; Device therapy

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