Effects of Catheter-Based Renal Denervation in Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes. We aimed to perform a comprehensive meta-analysis of all randomized, sham-controlled trials investigating RDN with first- and second-generation devices in hypertension. METHODS: We searched MEDLINE and the Cochrane Library for eligible trials. Outcomes included both efficacy (24-hour and office systolic [SBP] and diastolic blood pressure [DBP]) and safety (all-cause death, vascular complication, renal artery stenosis >70%, hypertensive crisis) of RDN. We performed a study-level, pairwise, random-effects meta-analysis of the summary data. RESULTS: Ten trials comprising 2478 patients with hypertension while being either off or on treatment were included. Compared with sham, RDN reduced 24-hour and office systolic blood pressure by 4.4 mm Hg (95% CI, 2.7 to 6.1; P<0.00001) and 6.6 mm Hg (95% CI, 3.6 to 9.7; P<0.0001), respectively. The 24-hour and office diastolic blood pressure paralleled these findings (-2.6 mm Hg [95% CI, -3.6 to -1.5]; P<0.00001; -3.5 mm Hg [95% CI, -5.4 to -1.6]; P=0.0003). There was no difference in 24-hour and office systolic blood pressure reduction between trials with and without concomitant antihypertensive medication (P for interaction, 0.62 and 0.73, respectively). There was no relevant difference in vascular complications (odds ratio, 1.69 [95% CI, 0.57 to 5.0]; P=0.34), renal artery stenosis (odds ratio, 1.50 [95% CI, 0.06 to 36.97]; P=0.80), hypertensive crisis (odds ratio, 0.65 [95% CI, 0.30 to 1.38]; P=0.26), and all-cause death (odds ratio, 1.76 [95% CI, 0.34 to 9.20]; P=0.50) between RDN and sham groups. Change of renal function based on estimated glomerular filtration rate was comparable between groups (P for interaction, 0.84). There was significant heterogeneity between trials. CONCLUSIONS: RDN safely reduces ambulatory and office systolic blood pressure/diastolic blood pressure versus a sham procedure in the presence and absence of antihypertensive medication.

The Efficacy of Renal Denervation in Treating Resistant Hypertension: A Systematic Review.

Resistant hypertension is blood pressure (BP) that is persistently above target in spite of the maximally tolerated usage of at least three anti-hypertensives simultaneously. The sympathetic nervous system is instrumental in blood pressure (BP) regulation. Renal (sympathetic) denervation involves using ablative energy to disrupt the sympathetic nerves in renal arteries. This systematic review examines the efficacy of this treatment modality. Abiding by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, we conducted an extensive literature search in five databases, Cochrane Library, Google Scholar, PubMed, PubMed Central (PMC), and ScienceDirect, to retrieve studies that are free, open access, and published in English done within the past four years. Nineteen articles passed critical appraisal. These articles were randomized controlled trials (RCT), a case report, a cross-sectional study, a cohort study, and previous reviews. Renal denervation (RDN) was generally superior to sham control in patients with resistant hypertension for reducing various systolic blood pressure (SBP) measures, including 24-hour ambulatory, daytime, and nighttime SBP. The efficacy was highest in patients whose baseline SBP was higher. BP reduction was sustained for years post-procedure. The procedure had a good safety profile with no severe complications. Future studies should compare the efficacy of different types of renal denervation, such as ethanol ablation versus radiofrequency ablation, and renal denervation against other procedure-based treatment modalities, such as carotid baroreceptor stimulation and transcranial direct current stimulation.

A Closed-Loop Nanosystem Based on Piezoelectric Sensor and Pd-Nanoshell Photothermal Ablation for Renal Denervation to Treat Hypertension.

Renal sympathetic nerves play a crucial role in the pathogenesis of hypertension, and renal denervation (RDN) is a new solution for patients with refractory hypertension. However, current RDN techniques show inconsistent results in clinical application probably owing to incomplete endovascular ablation of the sympathetic nerves and a lack of measures to localize and assess efficacy. In this study, a closed-loop RDN system consisting of a sensing unit with a piezoelectric thin-film sensor (PTFS) and a treatment unit with a hollow Pd nanoparticle shell (PdNPS) with a diameter of 202.0 nm for photothermal neural ablation is constructed. The PTFS can monitor and collect arterial pulsation and blood pressure (BP) and direct PdNPS to maximize RDN. PdNPS maintains a local temperature of 58-62 °C under near-infrared-II irradiation (1,064 nm) to achieve effective RDN within a range of 90-120 s treatment window. Photothermal ablation significantly inhibits the activities of renal sympathetic nerves post-procedure and after one month and reduces the elevation of BP by > 50%. The novel closed-loop system enables safe and efficient targeting, dynamic monitoring, and ablation of the renal sympathetic nerves. This closed-loop system provides a new strategy for RDN technology and even for treating sympathetic nerve-related chronic diseases.

Management of Renovascular Hypertension and Renal Denervation in Patients with Hypertension: An Italian Nationwide Survey.

INTRODUCTION: Renovascular hypertension (RVH) remains underdiagnosed despite its significant cardiovascular and renal morbidity. AIM: This survey investigated screening and management practices for RVH among hypertensive patients in Italian hypertension centres in a real-life setting. Secondary, we analysed the current spread of renal denervation (RDN) and the criteria used for its eligibility. METHODS: A 12 item-questionnaire was sent to hypertension centres belonging to the European Society of Hypertension and to the Italian Society of Hypertension (SIIA) in Italy. Data concerning the screening and management of RVH and of RDN were analysed according to the type of centre (excellence vs non-excellence centres), geographical area and medical specialty. RESULTS: Eighty-two centres participated to the survey. The number of patients diagnosed in each centre with RVH and fibromuscular dysplasia during the last five years was 3 [1;6] and 1 [0;2], respectively. Despite higher rates of RVH diagnosis in excellence centres (p = 0.017), overall numbers remained unacceptably low, when compared to expected prevalence estimates. Screening rates were inadequate, particularly among young hypertensive patients, with only 28% of the centres screening for RVH in such population. Renal duplex ultrasound was underused, with computed tomographic angiography or magnetic resonance angiography reserved for confirming a RVH diagnosis (76.8%) rather than for screening (1.9-32.7%, according to patients' characteristics). Scepticism and logistical challenges limited RDN widespread adoption. CONCLUSIONS: These findings underscore the need for improving RVH screening strategies and for a wider use of related diagnostic tools. Enhanced awareness and adherence to guidelines are crucial to identifying renovascular hypertension and mitigating associated cardiovascular and renal risks.

Research status and frontiers of renal denervation for hypertension: a bibliometric analysis from 2004 to 2023.

BACKGROUND: Renal Denervation (RDN) is a novel non-pharmacological technique to treat hypertension. This technique lowers blood pressure by blocking the sympathetic nerve fibers around the renal artery, then causing a decrease in system sympathetic nerve excitability. This study aimed to visualize and analyze research hotspots and development trends in the field of RDN for hypertension through bibliometric analysis. METHODS: In total, 1479 studies were retrieved on the Web of Science Core Collection (WoSCC) database from 2004 to 2023. Using CiteSpace (6.2.R4) and VOSviewer (1.6.18), visualization maps were generated by relevant literature in the field of RDN for hypertension to demonstrate the research status and frontiers. RESULTS: The number of publications was found to be generally increasing. Europe and the United States were the first countries to carry out research on different techniques and related RDN clinical trials. The efficacy and safety of RDN have been repeatedly verified and gained increasing attention. The study involves multiple disciplines, including the cardiovascular system, peripheral vascular disease, and physiological pathology, among others. Research hotspots focus on elucidating the mechanism of RDN in the treatment of hypertension and the advantages of RDN in appliance therapy. Additionally, the research frontiers include improvement of RDN instruments and techniques, as well as exploration of the therapeutic effects of RDN in diseases with increased sympathetic nerve activity. CONCLUSION: The research hotspots and frontiers reflect the status and development trend of RDN in hypertension. In the future, it is necessary to strengthen international collaboration and cooperation, conduct long-term clinical studies with a large sample size, and continuously improve RDN technology and devices. These measures will provide new options for more patients with hypertension, thereby improving their quality of life.

Effects of bilateral renal denervation on open-loop baroreflex function and urine excretion in spontaneously hypertensive rats.

Bilateral renal denervation (RDN) decreases arterial pressure (AP) or delays the development of hypertension in spontaneously hypertensive rats (SHR), but whether bilateral RDN significantly modifies urine output function during baroreflex-mediated acute AP changes remains unknown. We quantified the relationship between AP and normalized urine flow (nUF) in SHR that underwent bilateral RDN (n = 9) and compared the results with those in sham-operated SHR (n = 9). Moreover, we examined the acute effect of an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) on the AP-nUF relationship. Bilateral RDN significantly decreased AP by narrowing the response range of the total arc of the carotid sinus baroreflex. The slopes of nUF versus the mean AP (in µL·min-1·kg-1·mmHg-1) in the sham and RDN groups under baseline conditions were 0.076 ± 0.045 and 0.188 ± 0.039, respectively; and those after telmisartan administration were 0.285 ± 0.034 and 0.416 ± 0.078, respectively. The effect of RDN on the nUF slope was marginally significant (P = 0.059), which may have improved the controllability of urine output in the RDN group. The effect of telmisartan on the nUF slope was significant (P < 0.001) in the sham and RDN groups, signifying the contribution of circulating or locally produced angiotensin II to determining urine output function regardless of ongoing renal sympathetic nerve activity.

Autonomic neuromodulation for cardiomyopathy associated with metabolic syndrome - Prevention of precursors for heart failure with preserved ejection fraction.

Metabolic syndrome (MetS) induces a systemic inflammatory state which can lead to cardiomyopathy, manifesting clinically as heart failure (HF) with preserved ejection fraction (HFpEF). MetS components are intricately linked to the pathophysiologic processes of myocardial remodeling. Increased sympathetic nervous system activity, which is noted as an upstream factor of MetS, has been linked to adverse myocardial structural changes. Since renal denervation and vagus nerve stimulation have a sympathoinhibitory effect, attention has been paid to the cardioprotective effects of autonomic neuromodulation. In this review, the pathophysiology underlying the relationship between MetS and HF is elucidated, and the evidence regarding autonomic neuromodulation in HFpEF is summarized.

Options for patients with out-of-control blood pressure: after all avenues have been exhausted.

INTRODUCTION: Uncontrolled hypertension is the leading risk factor for global mortality. Most hypertensive patients can be controlled with standard medication combinations, but some may not respond adequately to ≥3 or even to ≥5 antihypertensive agents. AREAS COVERED: In this review, we summarize the recent literature on difficult-to-treat hypertension identified by a Medline search, and we discuss the options for fourth line and subsequent therapy. EXPERT OPINION: It is essential to confirm resistant hypertension with out-of-office blood pressure measurements and to consider lifestyle factors, adherence to medication and secondary causes of hypertension. When true resistant hypertension is confirmed and blood pressure is not controlled with an optimal triple combination, preferably as a fixed dose combination tablet, spironolactone is usually recommended as the fourth medication. Comorbid conditions should be treated as appropriate with sodium-glucose-cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, sacubitril-valsartan or finerenone. Renal denervation appears to be a useful addition to overcome some of the problems of medication adherence. The endothelin antagonist aprocitentan may be a final option in some countries. Of the drugs in development, the RNA based therapeutics that inhibit angiotensinogen synthesis appear to be some of the most promising.

Renal denervation achieves its antiarrhythmic effect through attenuating macrophage activation and neuroinflammation in stellate ganglia in chronic heart failure.

AIMS: Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for its antiarrhythmic effect are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study investigates if and how RDN decreases ventricular arrhythmias by attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. METHODS AND RESULTS: Rat CHF was induced by surgical ligation of the left anterior descending coronary artery (LAD). At 12 weeks after LAD ligation, completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein, followed by applying of 70% ethanol around the vessels. Immunofluorescence staining and Western blot data showed that expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor-α subunit (GM-CSFRα) in SGs was increased in CHF rats. RDN not only reduced CHF-elevated GM-CSF levels in kidney, serum and SGs, but also attenuated macrophage expansion and neuroinflammation in SGs from CHF rats. Using flow cytometry, we confirmed that RDN reduced the percentage of macrophages in SGs, which is pathologically increased in CHF. RDN also decreased CHF-enhanced N-type Ca2+ currents in CSP neurons and attenuated CHF-elevated cardiac sympathetic nerve activity. ECG data from 24-hour continuous telemetry recording in conscious rats revealed that RDN improved CHF-induced heterogeneity of ventricular electrical activities and reduced the duration of spontaneous ventricular tachyarrhythmias in CHF rats. CONCLUSIONS: RDN alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis through attenuating GM-CSF-induced macrophage activation and neuroinflammation within SGs in CHF. This suggests that manipulation of the GM-CSF signaling pathway could be a novel strategy for achieving the antiarrhythmic effect of RDN in CHF.

Catheter-based renal denervation in the treatment of arterial hypertension: An expert consensus statement on behalf of the French Society of Hypertension (SFHTA), French Society of Radiology (SFR), French Society of Interventional Cardiology (GACI), French Society of Cardiology (SFC), French Association of Private Cardiologists (CNCF), French Association of Hospital Cardiologists (CNCH), French Society of Thoracic and Cardiovascular Surgery (SFCTCV) and French Society of Vascular and Endovascular Surgery (SCVE).

Several high-quality, randomized, sham-controlled trials have provided evidence supporting the efficacy and safety of radiofrequency, ultrasound and alcohol catheter-based renal denervation (RDN) for reducing blood pressure (BP). A French clinical consensus document has therefore been developed to propose guidance for the appropriate use of RDN in the management of hypertension along with a dedicated care pathway and management strategy. The French experts group concluded that RDN can serve as an adjunct therapy for patients with confirmed uncontrolled, resistant essential hypertension despite treatment with≥3 antihypertensive drugs, including a long-acting calcium channel blocker, a renin-angiotensin system blocker and a thiazide/thiazide-like diuretic at maximally tolerated doses. Patients should have (1) an estimated glomerular filtration rate of≥40mL/min/1.73m2; (2) an eligible renal artery anatomy on pre-RDN scans and (3) exclusion of secondary forms of hypertension. Additional indications might be considered for patients with difficult-to-control hypertension. Any indication of RDN should be validated by multidisciplinary hypertension teams consisting of both hypertension specialists and endovascular interventionalists in European Society of Hypertension (ESH) Excellence Centres or ESH-BP clinics. Patients should be informed about the benefit/risk ratio of RDN. Expertise in renal artery interventions and training in RDN techniques are needed for endovascular interventionalists conducting RDN procedures while centres offering RDN should have the necessary resources to manage potential complications effectively. Lastly, all patients undergoing RDN should have their data collected in a nationwide French registry to facilitate monitoring and evaluation of RDN outcomes, contributing to ongoing research and quality improvement efforts.

36-month durability of ultrasound renal denervation for hypertension resistant to combination therapy in RADIANCE-HTN TRIO.

Endovascular ultrasound renal denervation (uRDN) reduced blood pressure (BP) compared to sham at 2 months in patients with resistant hypertension in the multicenter, blinded, randomized, sham-controlled RADIANCE-HTN TRIO trial. This analysis evaluates longer-term outcomes of patients randomized to uRDN. Patients with resistant hypertension to a 3-drug combination pill were randomized to uRDN (n = 69) or sham (n = 67). From 2-5 months, patients followed a standardized anti-hypertensive medication (AHM) titration protocol. At 6 months, patients were unblinded and received AHM per standard of care. In the uRDN group, 71% (49/69) completed 36-month follow-up. Screening office BP was 159/103 on 3.9 AHM. Baseline office BP on the single-pill combination was 153/99 mmHg. At 36 months, office BP changed by -14.5 ± 26.1/-9.0 ± 14.8 mmHg from screening (p < 0.001 for both) and -8.0 ± 24.5/-5.0 ± 14.6 mmHg from baseline (p = 0.007; p = 0.022) on 3.7 AHM. The efficacy of uRDN was durable to 36 months in patients with resistant hypertension with no safety concerns.

Robot-assisted renal denervation as a new surgical approach for therapy resistant arterial hypertension.

Arterial hypertension is a major cause of mortality and morbidity worldwide. Medical therapy is the most common treatment. However, in some cases there is a persistent high blood pressure despite medical therapy. These patients with medication refractory arterial hypertension can be treated by renal denervation. Until now an endovascular approach has been used. There are however limitations in eligibility based on vascular or anatomical anomalies. For these patients, as well as other patients eligible for renal denervation, robot-assisted renal denervation has the potential to become a surgical treatment option based on our findings.

Indications for renal denervation in the treatment of hypertension.

Renal denervation (RDN) is a neuromodulation therapy performed using an intraarterial catheter in patients with hypertension. Recent randomized sham-operated controlled trials have shown that RDN has significant antihypertensive effects in patients with resistant, uncontrolled, and/or drug-naïve hypertension. Based on available evidence, the European Society of Hypertension 2023 guidelines include a Class II recommendation for the use of RDN in individuals with resistant and uncontrolled hypertension. The US Food and Drug Administration approved two devices, the ultrasound-based ReCor ParadiseTM RDN system and the radiofrequency-based Medtronic Symplicity SpyralTM RDN system, as adjunctive therapy for patients with resistant and uncontrolled hypertension. The indications for RDN and incorporation of RDN into clinical practice will grow as clinical evidence accumulates. This mini review summarizes latest findings focusing on the safety and effectiveness of RDN for treating hypertension in the absence and presence of antihypertensive drugs, and discusses the indications for RDN. This mini review focuses on the safety and effectiveness of RDN for treating hypertension in the absence and presence of antihypertensive drugs. The indications for RDN and incorporation of RDN into clinical practice will grow as clinical evidence accumulates and should be reviewed and updated.

Randomized Trials of Renal Denervation for Uncontrolled Hypertension: An Updated Meta-Analysis.

BACKGROUND: Despite optimal medical therapy, a significant proportion of patients' blood pressure remains uncontrolled. Catheter-based renal denervation (RDN) has been proposed as a potential intervention for uncontrolled hypertension. We conducted an updated meta-analysis to assess the efficacy and safety of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off antihypertensive medications. METHODS AND RESULTS: Online databases were searched to identify randomized clinical trials comparing efficacy and safety of RDN versus control in patients with uncontrolled hypertension. Subgroup analyses were conducted for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking US Food and Drug Administration approval. Fifteen trials with 2581 patients (RDN, 1723; sham, 858) were included. In patients off antihypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory (-3.70 [95% CI, -5.41 to -2.00] mm Hg), office (-4.76 [95% CI, -7.57 to -1.94] mm Hg), and home (-3.28 [95% CI, -5.96 to -0.61] mm Hg) systolic blood pressures was noted. In patients on antihypertensive medications, a significant reduction was observed in 24-hour ambulatory (-2.23 [95% CI, -3.56 to -0.90] mm Hg), office (-6.39 [95% CI, -11.49 to -1.30]), home (-6.08 [95% CI, -11.54 to -0.61] mm Hg), daytime (-2.62 [95% CI, -4.14 to -1.11]), and nighttime (-2.70 [95% CI, -5.13 to -0.27]) systolic blood pressures, as well as 24-hour ambulatory (-1.16 [95% CI, -1.96 to -0.35]), office (-3.17 [95% CI, -5.54 to -0.80]), and daytime (-1.47 [95% CI, -2.50 to -0.27]) diastolic blood pressures. CONCLUSIONS: RDN significantly lowers blood pressure in patients with uncontrolled hypertension, in patients off and on antihypertensive medications, with a favorable safety profile. The efficacy of RDN was consistent in sham-controlled trials and contemporary trials using US Food and Drug Administration-approved devices.

Hypertension and Device-Based Therapies for Resistant Hypertension: An Up-to-Date Review.

Hypertension is the most prevalent modifiable risk factor associated with cardiovascular mortality. The World Health Organization (WHO) estimates that hypertension directly or indirectly causes the death of at least nine million people globally every year. The number of people living with hypertension (blood pressure (BP) of ≥140 mmHg systolic or ≥90 mmHg diastolic or on medication) doubled between 1990 and 2019, from 650 million to 1.3 billion. Despite a plethora of antihypertensive drugs widely available, a sizable part of the antihypertensive population stays uncontrolled. The unmet need of controlling BP in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. Several device-based approaches have been introduced to lower BP, and most of these strategies aim to modulate autonomic nervous system activity. Importantly, when considering a device-based treatment, each patient's underlying pathophysiology is considered, and the procedural risks are weighed against the cardiovascular risk attributed to the elevated BP. In November 2023, the FDA approved two renal denervation (RDN) devices. This manuscript discusses current interventional devices and procedures recently approved (RDN) and others in the clinical testing stage for arterial hypertension intervention or management. As we list below, all others have shown promising results and are being evaluated on a larger clinical trial. The new device-based classes are as follows: catheter-based RDN, baroreflex amplification, arteriovenous (AV) malformation, carotid body (CB) ablation, pacemaker-based cardiac neuromodulation, electro-acupuncture, and deep brain stimulation. Baroreflex amplification uses peripheral neuromodulation, while AV malformation leverages AV anastomosis. CB ablation modulates chemoreceptors, and pacemaker-based neuromodulation adjusts atrioventricular intervals. Electro-acupuncture proves potential, and deep brain stimulation offers central nervous system intervention.

Efficacy of renal denervation as an adjunct to pulmonary vein isolation for atrial fibrillation treatment: a systematic review and meta-analysis.

Aims: Catheter ablation, consisting of pulmonary vein isolation (PVI), is the most effective treatment modality for the management of symptomatic patients with atrial fibrillation (AF). Unfortunately, this procedure has a considerable relapse rate, ranging from 15 to 50% depending on AF type and other patient factors. Hypertension (HTN) is associated with a higher risk of developing AF and can also be managed with a catheter-based procedure-renal denervation (RDN). This meta-analysis aimed to compare the effect of PVI with and without RDN in hypertensive patients with AF. Methods and results: OVID MEDLINE and Embase were searched on 1 February 2023 and trials that reported the effects of RDN on AF recurrence in hypertensive patients were included. A total of 637 patients across 8 randomised controlled trials were included. The results from the pooled analysis showed that when compared with PVI alone, RDN added to PVI: (1) Lowered AF recurrence [RR 0.67 (0.53, 0.85), P = 0.001, I 2 = 23%, NNT = 5.9 patients]; (2) Reduced both systolic blood pressure and diastolic blood pressure, with medium effect size, as reflected by standardised mean differences of 0.5 (P = 0.02, I 2 = 80%) and 0.43 (P = 0.006, I 2 = 60%), respectively; and (3) was not associated with a decrease in estimated glomerular filtration rate (+7.19 mL/min/1.73 m2, P = 0.15, I 2 = 89%). Conclusion: Adding RDN to PVI in patients with AF and resistant HTN was associated with a reduction of blood pressure levels and AF recurrence. Consideration to RDN should be given as an adjunctive treatment for patients with AF and resistant HTN.