Novel drug and device therapies have the potential to achieve long-term control of blood pressure (BP) and thereby overcome the barriers of nonadherence and undertreatment. We propose that ideal BP lowering therapy should meet six key criteria: (i) achieve a clinically relevant BP reduction; (ii) durable BP reduction; (iii) be well tolerated; (iv) have the ability to be safely combined with other BP lowering treatments; (v) have high patient acceptability and (vi) be cost-effective and simple to use to maximize scalability. In this paper, we systematically review emerging solutions for long-term control of BP including antibody-based therapies, sRNA therapies, and DNA-based gene editing which target the renin angiotensin system, and implant therapies, and interventional approaches (renal denervation and baroreceptor activation therapies). These novel therapies may substantially complement and, in some settings, even replace current antihypertensive therapies. Implementation will require significant progress in overcoming technological-, systems-, prescriber- and patient-level barriers.

The principle of NetrodTM Renal Denervation RF Generator is based on the heating of radiofrequency electrodes to achieve the therapeutic temperature for peripheral nerve ablation with minimal impact on intra-arterial blood flow. The extravascular heat distribution and continuous ablation were evaluated using COMSOL Multiphysics with an idealized 3D model and validated in an ex vivo experiment. The safety of ablation was verified by H&E staining of a hypertensive dog model in the treatment group of animal experiments, and changes in blood pressure before and after the procedure(assessed at 7, 30, and 60 days in animal experiments) were used to characterize the efficacy. The simulation results showed that the maximum injury depth range of the NetrodTM Six-electrode is 5.08mm and the depth of the ablation zone obtained in the Phantom experiment was 3-6mm. Circumferential coverage was up to 91.99% and the ablation zone was continuous. In animal experiments, eight animals in the treatment group had significantly lower blood pressure (88.9%). Nerve cells in nerve bundles showed vacuolar changes and thickening of peripheral sheaths after peripheral nerve ablation of renal arteries.The NetrodTM Six-electrode presented here has potential to effectively and safely ablate renal nerves. The demonstrated efficacy and safety in animal models provide a foundation for clinical trials in humans.

Activation of the sympathetic nervous system has been attributed to the development of hypertension. Two established approaches for treating hypertension are pharmacotherapy and lifestyle changes. With an improved understanding of renal nerve anatomy and physiology, renal denervation has been proposed as an alternative treatment for hypertension. Specifically, it has been shown that the interruption of sympathetic nerves connecting the kidney and the sympathetic nervous system can reduce blood pressure. Here, we present a review on how renal denervation can help hypertension patients, specifically focusing on our novel understanding of renal nerve anatomy, denervation technique, and subsequent clinical trials, and how it may be used to treat other cardiovascular diseases like heart failure.

Renal denervation (RDN) lowers blood pressure (BP) in patients with uncontrolled hypertension. Current guidelines recommend RDN for patients with uncontrolled BP despite the use of antihypertensive (AH) medications. Durability of BP reductions and assessment of which patient baseline characteristics correlate with subsequent BP reductions are scarce.

The authors leveraged patient data from the entire SYMPLICITY Clinical program to model long-term BP reductions and assess patient characteristics associated with future BP reductions.

Repeated BP measurements from each patient were analyzed using linear mixed models. Models were fitted with office systolic BP (SBP), 24-h ambulatory SBP, office diastolic BP (DBP), and 24-h ambulatory DBP as outcome variables. Baseline BP, baseline number of AH medications, AH medications over time, and other variables were included as fixed effects.

The mixed model included data from 4,155 patients treated with the Symplicity RDN system. The mean age was 60 ± 12 years, 40.4% of whom were female. Estimated, longitudinal office and 24-h ambulatory SBP changes through 36 months, after adjusting for AH medication effects, were biphasic, with a steep reduction after RDN through the first 6 months followed by continuous and steady reductions in office and 24-h SBP and DBP afterward through 36 months. Higher baseline office systolic or 24-h ambulatory SBP were correlated with greater reductions through follow-up in office and 24-h SBP, respectively. Patient characteristics consistent with high sympathetic nerve activity, such as atrial fibrillation and type 2 diabetes, emerged as statistically significant covariates associated with greater office systolic and office and 24-h diastolic BP reductions, respectively.

Modeling suggested patients have durable BP reductions following RDN, with a steep immediate reduction followed by a steady reduction through 3 years.

Renal denervation as an option for difficult to treat hypertension has been a concept for several decades, with recent U.S. FDA approval of new, minimally invasive devices. However, while renal denervation has the potential to improve hypertension management, several challenges require consideration prior to widespread adoption. The effect relative to sham control is modest, and generally similar to addition of a single blood pressure lowering medication. It is possible that with additional technique refinement greater effects may be possible. Key factors to consider beyond the direction, strengths, and limitations of the renal denervation technologies themselves, are an understanding of patient groups that derive greatest benefit and phenotypes or biomarkers that predict greater response. This review provides an update on these challenges in addition to the current state and future of renal denervation within the context of hypertension management and treatment.

Renal artery denervation has re-emerged as a potential therapeutic option for patients with hypertension, especially those resistant to conventional pharmacotherapy. This comprehensive review explores the importance of careful patient selection, procedural techniques, clinical efficacy, safety considerations, and future directions of renal artery denervation in hypertension management. Drawing upon a wide range of available evidence, this review aims to provide a thorough understanding of the procedure and its role in contemporary hypertension treatment paradigms.

This study aimed to systematically evaluate the effectiveness and safety of renal denervation (RDN) in managing heart failure with reduced ejection fraction (HFrEF).

A comprehensive search was done in multiple databases: Cochrane Library, PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database for Chinese Technical Periodicals. All clinical trials investigating RDN treatment for HFrEF through 15 March 2024 were gathered. The quality of the included studies was evaluated utilizing the Cochrane risk assessment tool. The pertinent data were gathered, and a meta-analysis was done using Review Manager 5.3, accompanied by sensitivity and publication bias analyses.

After applying the inclusion and exclusion criteria, eight randomized controlled trials (RCTs) were selected for analysis, encompassing 314 patients; 154 patients underwent RDN treatment during hospitalization, while 150 were randomized to the control group to receive medication therapy. The meta-analysis demonstrated that compared to medication therapy, RDN contributed to a 9.59% increase in left ventricular ejection fraction (LVEF) (95% CI: 7.92-11.27, Z = 11.20, p < 0.01); a decrease in brain natriuretic peptide (BNP) (95% CI: -364.19--191.75, Z = 6.32, p < 0.01); a decrease in N-terminal pro B-type natriuretic peptide (NT-proBNP) (95% CI: -1300.15--280.95, Z = 3.04, p < 0.01); a decrease in the New York Heart Association (NYHA) classification (95% CI: -1.58--0.34, Z = 3.05, p < 0.01); a 90.00-m increase in 6-min walk test (6MWT) (95% CI: 68.24-111.76, Z = 8.11, p < 0.01); a reduction of 4.05 mm in left ventricular end-diastolic diameter (LVEDD) (95% CI: -5.65--2.48, Z = 5.05, p < 0.01); a decrease of 4.60 heart beats·min-1 (95% CI: -8.83--0.38, Z = 2.14, p < 0.05); and a 4.67-mm reduction in left atrial diameter (LAD) (95% CI: -6.40--2.93, Z = 5.27, p < 0.01). Left ventricular end-systolic diameter (LVESD) and systolic/diastolic blood pressure (OSBP/ODBP) were similar between groups (p > 0.01). As the safety indicator, estimated glomerular filtration rate (eGFR) improved by 7.11 in the RDN group [ml/(min·1.73 m2)] (95% CI: 1.10-13.12, Z = 2.32, p < 0.05). LVEF, BNP, 6MWT, LVEDD, LAD and eGFR were meta-analyzed using a fixed-effects model, the other indicators a random-effects model.

RDN significantly ameliorated cardiac function in HFrEF patients while exhibiting commendable safety.

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.

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.

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.

RDN safely reduces ambulatory and office systolic blood pressure/diastolic blood pressure versus a sham procedure in the presence and absence of antihypertensive medications.

The kidneys act as finely tuned sensors to maintain physiological homeostasis. Both sympathetic and sensory nerves modulate kidney function through precise neural control. However, how the kidneys are innervated during development to support function remains elusive. Using light-sheet and confocal microscopy, we generated anatomical maps of kidney innervation across development. Kidney innervation commences on embryonic day 13.5 (E13.5) as network growth aligns with arterial differentiation. Fibers are synapsin I+, highlighting ongoing axonogenesis and potential signaling crosstalk. By E17.5, axons associate with nephrons, and the network continues to expand postnatally. CGRP+, substance P+, TRPV1+, and PIEZO2+ sensory fibers and TH+ sympathetic fibers innervate the developing kidney. TH+ and PIEZO2+ axons similarly innervate the human kidney, following the arterial tree to reach targets. Retrograde tracing revealed the primary dorsal root ganglia, T10-L2, from which sensory neurons project to the kidneys. Together, our findings elucidate the temporality and neuronal diversity of kidney innervation.

Renal denervation (RDN) has emerged as a novel therapy for drug-resistant hypertension. We here examined the effects of RDN at early versus advanced stages of hypertension on blood pressure and organ pathology in rats with salt-sensitive hypertension. Dahl salt-sensitive (DahlS) rats fed an 8% NaCl diet from 6 weeks of age were subjected to RDN (surgical ablation and application of 10% phenol in ethanol) or sham surgery at 7 (early stage) or 9 (advanced stage) weeks and were studied at 12 weeks. RDN at early or advanced stages resulted in a moderate lowering of blood pressure. Although RDN at neither stage affected left ventricular (LV) and cardiomyocyte hypertrophy, it ameliorated LV diastolic dysfunction, fibrosis, and inflammation at both stages. Intervention at both stages also attenuated renal injury as well as downregulated the expression of angiotensinogen and angiotensin-converting enzyme (ACE) genes and angiotensin II type 1 receptor protein in the kidney. Furthermore, RDN at both stages inhibited proinflammatory gene expression in adipose tissue. The early intervention reduced both visceral fat mass and adipocyte size in association with downregulation of angiotensinogen and ACE gene expression. In contrast, the late intervention increased fat mass without affecting adipocyte size as well as attenuated angiotensinogen and ACE gene expression. Our results thus indicate that RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated cardiac and renal injury and adipose tissue inflammation in DahlS rats. They also suggest that cross talk among the kidney, cardiovascular system, and adipose tissue may contribute to salt-sensitive hypertension. Supposed mechanism for the beneficial effects of RDN on hypertension and target organ damage in DahlS rats. RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated renal injury in DahlS rats. Cross talk among the kidney, cardiovascular system, and adipose tissue possibly mediated by circulating RAS may contribute to salt-sensitive hypertension. LV; left ventricular, NE; norepinephrine, RAS; renin-angiotensin system, RDN; renal denervation.

The efficacy of renal denervation (RDN) has been controversial, but recent randomized sham-controlled trials demonstrated significant blood pressure reductions after RDN in patients with hypertension. We conducted a systematic review and updated meta-analysis to evaluate the effects of RDN on ambulatory and office blood pressures in patients with hypertension. Databases were searched up to 15 November 2023 to identify randomized, sham-controlled trials of RDN. The primary endpoint was change in 24 h ambulatory systolic blood pressure (SBP) with RDN versus sham control. The secondary endpoints were changes in 24 h ambulatory diastolic blood pressure, daytime and nighttime blood pressure (BP), office BP, and home BP. A sub-analysis determined outcomes by medication, procedure, and device. From twelve trials, 2222 patients with hypertension were randomized to undergo RDN (n = 1295) or a sham procedure (n = 927). At 2-6 months after treatment, RDN significantly reduced 24 h ambulatory SBP by 2.81 mmHg (95% confidence interval: -4.09, -1.53; p < 0.001) compared with the sham procedure. RDN also reduced daytime SBP by 3.17 mmHg (- 4.75, - 1.58; p < 0.001), nighttime SBP by 3.41 mmHg (- 4.69, - 2.13; p < 0.001), office SBP by 4.95 mmHg (- 6.37, - 3.54; p < 0.001), and home SBP by 4.64 mmHg (- 7.44, - 1.84; p = 0.001) versus the sham control group. There were no significant differences in the magnitude of BP reduction between first- and second-generation trials, between devices, or between with or without medication. These data from randomized sham-controlled trials showed that RDN significantly reduced all blood pressure metrics in medicated or unmedicated patients with hypertension, including resistant/uncontrolled hypertension.

Catheter based renal denervation has recently been FDA approved for the treatment of hypertension. Traditionally, the anti-hypertensive effects of renal denervation have been attributed to the ablation of the efferent sympathetic renal nerves. In recent years the role of the afferent sensory renal nerves in the regulation of blood pressure has received increased attention. In addition, afferent renal denervation is associated with reductions in sympathetic nervous system activity. This suggests that reductions in sympathetic drive to organs other than the kidney may contribute to the non-renal beneficial effects observed in clinical trials of catheter based renal denervation. In this review we will provide an overview of the role of the afferent renal nerves in the regulation of renal function and the development of pathophysiologies, both renal and non-renal. We will also describe the central projections of the afferent renal nerves, to give context to the responses seen following their ablation and activation. Finally, we will discuss the emerging role of the kidney as an interoceptive organ. We will describe the potential role of the kidney in the regulation of interoceptive sensitivity and in this context, speculate on the possible pathological consequences of altered renal function.

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.

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.

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.

Hypertension (HTN) is a major contributor to cardiovascular mortality. Many patients with drug-resistant hypertension (DRH) also require permanent pacing (PP). This large retrospective study evaluated the effect of PP for conventional PP indications in older patients with DRH. We reviewed the charts of 176 patients with dual-chamber PP and DRH. The effects of PP on systolic and diastolic blood pressure (sBP and dBP), the number of HTN-related medications, and left ventricular ejection fraction (LVEF) were assessed at 6 months post-implantation and compared with pre-implantation values. Patients were followed up with for ≥72 months. Patients with a decline of >5 mmHg in sBP and decrease in at least one anti-HTN medication were defined as responders (126/176; P < .01). The mean decline in sBP was 9 mmHg, while that in dBP was 3 mmHg (P < .001 for both). Among responders, optimal reductions in sBP, dBP, and medications were seen at a stratification of >50% atrial pacing and <40% ventricular pacing (-12, -6.3, and -1.6, respectively). When right ventricular pacing of <50% was used for dichotomizing, the optimal atrial/ventricular pacing stratification was atrial pacing > 50% and ventricular pacing < 40% (-11.3, -6.3, and -1.6, respectively). A relationship between increasing atrial pacing and a decline in sBP was noted but did not reach statistical significance. However, of those responders who had a >10-mmHg decline in sBP, the majority were paced between 60%-100% in the atria. The LVEF did not change post-PP in either group. In conclusion, PP results in significant improvement in BP control. The observed association warrants further investigation.

Resistant hypertension (RH) includes hypertensive patients with uncontrolled blood pressure (BP) while receiving ≥3 BP-lowering medications or with controlled BP while receiving ≥4 BP-lowering medications. The exact prevalence of RH is challenging to quantify. However, a reasonable estimate of true RH is around 5% of the hypertensive population. Patients with RH have higher cardiovascular risk as compared with hypertensive patients in general. Standardized office BP measurement, confirmation of medical adherence, search for drug- or substance-induced BP elevation, and ambulatory or home BP monitoring are mandatory to exclude pseudoresistance. Appropriate further investigations, guided by clinical data, should be pursued to exclude possible secondary causes of hypertension. The management of RH includes the intensification of lifestyle interventions and the modification of antihypertensive drug regimens. The essential aspects of lifestyle modification include sodium restriction, body weight control, regular exercise, and healthy sleep. Step-by-step adjustment of the BP-lowering drugs based on the available evidence is proposed. The suitable choice of diuretics according to patients' renal function is presented. Sacubitril/valsartan can be carefully substituted for the prior renin-angiotensin system blockers, especially in those with heart failure with preserved ejection fraction. If BP remains uncontrolled, device therapy such as renal nerve denervation should be considered. Since device-based treatment is an invasive and costly procedure, it should be used only after careful and appropriate case selection. In real-world practice, the management of RH should be individualized depending on each patient's characteristics.

Renal denervation may be indicated in patients with treatment-resistant essential hypertension to decrease sympathetic nervous activity and optimise blood pressure. We present the case of a woman in her 50s with long-standing essential hypertension, a previous transient ischaemic attack, obesity and a family history of cardiovascular disease, who presented with persistent 24-hour ambulatory hypertension despite ongoing lifestyle modifications and being on five antihypertensive agents with no evidence of an alternative primary aetiology. She had intermittent palpitations and blurring of vision alongside evidence of left ventricular hypertrophy on a CT scan. She underwent renal denervation, following which, not only was she able to cease all antihypertensive therapy but managed to maintain optimised blood pressure with subsequent reversal of left ventricular hypertrophy. Trials have demonstrated modest but inconsistent reductions in blood pressure whereas our case represents a 'super-response' likely due to a higher number of circumferential ablations in comparison to previous studies.

Renal denervation (RDN) is a safe and effective strategy for the treatment of difficult to treat hypertension. The blood pressure (BP)-lowering efficacy of RDN is comparable to those of many single antihypertensive medications and it allows to consider the RDN as a valuable option for the treatment of difficult to treat hypertension together with lifestyle modifications and medical therapy. A multidisciplinary team is of pivotal importance from the selection of the patient candidate for the procedure to the post-procedural management. Further studies are needed to investigate the effect of RDN on clinical outcomes and to better identify the predictors of BP response to RDN in order to recognize the patients who are more likely to benefit from the procedure.

Hypertension is a primary contributor to cardiovascular disease, and the leading risk factor for loss of quality adjusted life years. Up to 50% of the cases of hypertension in the United States remain uncontrolled. Additionally, 8%-18% of the hypertensive population have resistant hypertension; uncontrolled pressure despite 3 different antihypertensive agents. Recently, catheter-based percutaneous renal denervation emerged as a method for ablating renal sympathetic nerves for difficult-to-control hypertension. Initial randomized (non-sham) trials and registry analyses showed impressive benefit, but the first sham-controlled randomized controlled trial using monopolar radiofrequency ablation showed limited benefit. With refinement of techniques to include multipolar radiofrequency, ultrasound denervation, and direct ethanol injection, randomized controlled trials demonstrated significant blood pressure improvement, leading to US Food and Drug Administration approval of radiofrequency- and ultrasound-based denervation technologies. In this review article, we summarize the major randomized sham-controlled trials and societal guidelines regarding the efficacy and safety of renal artery denervation for the treatment of uncontrolled hypertension.

Cardiovascular disease is the most common cause of death worldwide, resulting in millions of deaths annually. Currently, there are still some deficiencies in the treatment of cardiovascular diseases. Innovative surgical treatments are currently being developed and tested in response to this situation. Large animal models, which are similar to humans in terms of anatomy, physiology, and genetics, play a crucial role in connecting basic research and clinical applications. This article reviews recent preclinical studies and the latest clinical advancements in cardiovascular disease based on large animal models, with a focus on targeted delivery, neural regulation, cardiac remodeling, and hemodynamic regulation. It provides new perspectives and ideas for clinical translation and offers new methods for clinical treatment.

Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes.

To perform a comprehensive meta-analysis of all randomized, sham-controlled trials investigating RDN with first- and second-generation devices in hypertension.

We searched MEDLINE and 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.

Ten trials comprising 2,478 patients with hypertension while being either off- or on-treatment were included. Compared with sham, RDN reduced 24-hour and office systolic BP by 4.4 mmHg (95%CI -6.1, -2.7, p<0.00001) and 6.6 mmHg (95%CI -9.7, -3.6, p<0.0001), respectively. The 24-hour and office diastolic BP paralleled these findings (-2.6 mmHg, 95%CI - 3.6, -1.5, p<0.00001; -3.5 mmHg, 95%CI -5.4, -1.6, p=0.0003). There was no difference in 24-hour and office SBP reduction between trials with and without concomitant antihypertensive medication (p for interaction 0.62 and 0.73, respectively). There was no relevant difference concerning vascular complications (OR 1.69, 95%CI 0.57-5.0, p=0.34), renal artery stenosis (OR 1.50, 95%CI 0.06-36.97, p=0.80), hypertensive crisis (OR 0.65, 95%CI 0.30-1.38, p=0.26) and all-cause death (OR 1.76, 95%CI 0.34-9.20, p=0.50) between RDN and sham groups. Change of renal function based on eGFR was comparable between groups (p for interaction 0.84). There was significant heterogeneity between trials.

RDN safely reduces ambulatory and office SBP/DBP vs. a sham procedure in the presence and absence of antihypertensive medication.

What is new?Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes.This comprehensive meta-analysis comprising 2,478 patients shows that irrespective of the utilized method (radiofrequency-, ultrasound-or alcohol-mediated), renal denervation effectively reduced ambulatory and office systolic blood pressure.Renal denervation exhibited no additional risk concerning vascular injury or renal function impairment.What are the clinical implications?This meta-analysis supports current guidelines/consensus statements that renal denervation represents an additive treatment option in carefully selected patients with uncontrolled hypertension.

Resistant hypertension is diagnosed in patients whose blood pressure target is unmet despite the use of three or more antihypertensive medications. Systemic sympathetic hyperactivation is associated with the development of resistant hypertension. As the kidney is largely pervasive of the sympathetic nervous system renal denervation procedure was developed to control blood pressure by attenuating the renal and systemic sympathetic hyperactivity. Renal denervation is a minimally invasive procedure that uses radiofrequency or ultrasound energy waves to reduce the activity of the renal artery nerves. Previous clinical trials have shown conflicting results regarding the efficacy of the procedure. Symplicity HTN-1 and -2 trials showed effective blood pressure lowering results in the renal denervation group with a good safety profile. However, the Symplicity HTN-3 trial showed no difference in blood pressure lowering effect between the renal denervation and control Sham procedure groups. Notwithstanding, some recent clinical trials with Sham control and meta-analysis showed clinical benefits of renal denervation. Other clinical benefits of renal denervation include glucose control, cardiovascular protective effect, reduction of obstructive sleep apnea, and neuralgia control. A subset of patients with satisfactory blood pressure control response to the procedure may experience improved glucose control due to the overall reduced sympathetic activity and insulin resistance. Sympathetic activity control after renal denervation has cardioprotective effects, especially for those with arrhythmia and left ventricular hypertrophy. Also, renal denervation could be helpful in renalorigin pain control. Renal denervation is an effective, safe, non-invasive procedure with many clinical benefits beyond blood pressure control. Further development in the procedure technique and selection of target patients are needed for wider clinical use of renal denervation in resistant hypertension.

Renal Artery Sympathetic Denervation (RDN) can lower blood pressure. Different ablation catheters (single electrode, multi-electrode) have different scopes of ablation (renal artery main stem and branches). Few studies have compared the advantages and disadvantages of different ablation catheters and different procedures in terms of antihypertensive efficacy. To compare the efficacy and safety of 3D reconstruction radiofrequency ablation (3DRA) and basket multi-electrode radiofrequency ablation (BMRA) in Renal Artery Sympathetic Denervation. Fifty-three patients with Refractory hypertension (RHT) were divided into BMRA, (n = 28) and 3DRA(n = 25). BMRA group used a stereobasket multi-electrode ablation catheter with a controlled ablation temperature of 60°C and an ablation time of 120 s per site. 3DRA group used a NavStar pressure-monitored perfusion monopolar ablation catheter with a controlled ablation temperature of 40°C, an ablation time of 40 s per site, and an ablation energy of 12 W. Baseline and RDN parameters and complications were compared in both groups. Home and 24 h ambulatory blood pressure, type of anti-hypertensive medication taken, and serum creatinine were followed up at 1, 3, 6, 12, and 24 months after the RDN. There were no differences in baseline characteristics between the two groups. (23.14 ± 2.00)months of follow-up in the BMRA group resulted in a total of (25.86 ± 8.61) loci ablation. (19.28 ± 7.40)months of follow-up in the 3DRA group resulted in a total of (21.04 ± 6.47)loci ablation. Home SBP was significantly lower in both groups at 1 month after RDN treatment compared to baseline(H-SBP/mmHg: BMRA 149.9 ± 10.59 vs. baseline 168.36 ± 12.76; 3DRA 152.6 ± 14.91 vs. 164.89 ± 12.96, both p < .05). The proportion of people with 24 h ambulatory SBP attainment was significantly higher in both groups and was maintained for 24 months. At each follow-up time point, there were no differences in home and 24-h flow SBP, DBP, or Scr between the two groups. There were two cases of severe renal artery complications from implanted vascular stents and one case of femoral artery pseudoaneurysm in the 3DRA group. At follow-up, 1 (1.9%) patient in the 3DRA group died of unexplained death and 1 (1.9%) patient developed heart failure, and 1 (1.9%) patient in the BMRA group died of unexplained death. Basket multi-electrode radiofrequency ablation and 3D reconstruction radiofrequency ablation of the renal artery applied to RDN have comparable efficacy in reducing systolic blood pressure.

The kidney functions as a finely tuned sensor to balance body fluid composition and filter out waste through complex coordinated mechanisms. This versatility requires tight neural control, with innervating efferent nerves playing a crucial role in regulating blood flow, glomerular filtration rate, water and sodium reabsorption, and renin release. In turn sensory afferents provide feedback to the central nervous system for the modulation of cardiovascular function. However, the cells targeted by sensory afferents and the physiological sensing mechanisms remain poorly characterized. Moreover, how the kidney is innervated during development to establish these functions remains elusive. Here, we utilized a combination of light-sheet and confocal microscopy to generate anatomical maps of kidney sensory and sympathetic nerves throughout development and resolve the establishment of functional crosstalk. Our analyses revealed that kidney innervation initiates at embryonic day (E)13.5 as the nerves associate with vascular smooth muscle cells and follow arterial differentiation. By E17.5 axonal projections associate with kidney structures such as glomeruli and tubules and the network continues to expand postnatally. These nerves are synapsin I-positive, highlighting ongoing axonogenesis and the potential for functional crosstalk. We show that sensory and sympathetic nerves innervate the kidney concomitantly and classify the sensory fibers as calcitonin gene related peptide (CGRP)+, substance P+, TRPV1+, and PIEZO2+, establishing the presence of PIEZO2 mechanosensory fibers in the kidney. Using retrograde tracing, we identified the primary dorsal root ganglia, T10-L2, from which PIEZO2+ sensory afferents project to the kidney. Taken together our findings elucidate the temporality of kidney innervation and resolve the identity of kidney sympathetic and sensory nerves.

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension.

Renal denervation (RDN) is a minimally invasive intervention performed by denervation of the nervous fibers in the renal plexus, which decreases sympathetic activity. These sympathetic nerves influence various physiological functions that regulate blood pressure (BP), including intravascular volume, electrolyte composition, and vascular tone. Although proven effective in some trials, controversial trials, such as the Controlled Trial of Renal Denervation for Resistant Hypertension (SYMPLICITY-HTN3), have demonstrated contradictory results for the effectiveness of RDN in resistant hypertension (HTN). In the treatment of HTN, individuals with primary HTN are expected to experience greater benefits compared to those with secondary HTN due to the diverse underlying causes of secondary HTN. Beyond its application for HTN, RDN has also found utility in addressing cardiac arrhythmias, such as atrial fibrillation, and managing cases of heart failure. Non-cardiogenic applications of RDN include reducing the intensity of obstructive sleep apnea (OSA), overcoming insulin resistance, and in chronic kidney disease (CKD) patients. This article aims to provide a comprehensive review of RDN and its uses in cardiology and beyond, along with providing future directions and perspectives.

Our previous study reported that the heterodimer of Angiotensin II Type I Receptor (AT1R) and Mu-Opioid Receptor 1 (MOR1) involves Nitric Oxide (NO) reduction which leads to elevation of blood pressure. Secondly, we showed that Toll-like Receptor 4 (TLR4) may be involved in the heterodimerization of AT1R and MOR1 in the brainstem Nucleus Tractus Solitarii (NTS), which regulates systemic blood pressure and gastric nitric oxide through the insulin pathway. Here, we investigated the role of microglial activation and TLR4 in the heterodimerization of AT1R and MOR1. Hypertensive rats were established after four weeks of fructose consumption. SBP of rats was measured using non-invasive blood pressure method. PLA technique was utilized to determine protein-protein interaction in the nucleus tractus solitarii. Results showed that the level of MOR-1 and AT1R was induced significantly in the fructose group compared with control. PLA signal potentially showed that AT1R and MOR1 were formed in the nucleus tractus solitarii after fructose consumption. Meanwhile, the innate immune cell in the CNS microglia was observed in the nucleus tractus solitarii using biomarkers and was activated. TLR4 inhibitor CLI-095, was administered to animals to suppress the neuroinflammation and microglial activation. CLI-095 treatment reduced the heterodimer formation of AT1R and MOR1 and restored nitric oxide production in the nucleus tractus solitarii. These findings imply that TLR4-primed neuroinflammation involves formation of heterodimers AT1R and MOR1 in the nucleus tractus solitarii which leads to increase in systemic blood pressure.

Although reports vary, the prevalence of true resistant hypertension and apparent treatment-resistant hypertension (aTRH) has been reported to be 10.3% and 14.7%, respectively. As there is a rapid increase in the prevalence of obesity, chronic kidney disease, and diabetes mellitus, factors that are associated with resistant hypertension, the prevalence of resistant hypertension is expected to rise as well. Frequently, patients with aTRH have pseudoresistant hypertension [aTRH due to white-coat uncontrolled hypertension (WUCH), drug underdosing, poor adherence, and inaccurate office blood pressure (BP) measurements]. As the prevalence of WUCH is high among patients with aTRH, the use of out-of-office BP measurements, both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM), is essential to exclude WUCH. Non-adherence is especially problematic, and methods to assess adherence remain limited and often not clinically feasible. Therefore, the use of HBPM and higher utilization of single-pill fixed-dose combination treatments should be emphasized to improve drug adherence. In addition, primary aldosteronism and symptomatic obstructive sleep apnea are quite common in patients with hypertension and more so in patients with resistant hypertension. Screening for these diseases is essential, as the treatment of these secondary causes may help control BP in patients who are otherwise difficult to treat. Finally, a proper drug regimen combined with lifestyle modifications is essential to control BP in these patients.

Hypertension is the most potent modifiable risk factor for the development of cardiovascular morbidity and mortality worldwide. Nevertheless, blood pressure (BP) control on a broad scale appears to be insurmountable and has even worsened in the US. Barriers to sustained hypertension control are multifactorial and although lack of patient awareness and socioeconomic barriers to healthcare access may play a role, medication non-compliance and therapeutic inertia are major causes. Renal denervation (RDN) is a minimally invasive procedure that has been the subject of interest in clinical trials for more than a decade and although the first sham-controlled trial could not detect group difference between treated and untreated hypertensives, subsequent, better designed sham-controlled trials clearly demonstrated the BP lowering effect of RDN, as well as its safety. While to-date, RDN is not available for routine clinical practice, one major requirement for broad implementation is that the BP lowering effect is durable. Therefore, this review will summarize the available long-term data of the different RDN modalities with respect to both effectiveness and safety.

Renal denervation is not a cure for hypertension. Although more recent sham-controlled trials were positive, a significant minority of patients in each trial were unresponsive. The optimal patient or patients need to be defined. Combined systolic/diastolic hypertension appears more responsive than isolated systolic hypertension. It remains uncertain whether patients with comorbidities associated with higher adrenergic tone should be targeted, including obesity, diabetes, sleep apnea, and chronic kidney disease. No biomarker can adequately predict response. A key to a successful response is the adequacy of denervation, which currently cannot be assessed in real time. It is uncertain what is the optimal denervation methodology: radiofrequency, ultrasound, or ethanol injection. Radiofrequency requires targeting the distal main renal artery plus major branches and accessory arteries. Although denervation appears to be safe, conclusive data on quality of life, improved target organ damage, and reduced cardiovascular events/mortality are required before denervation can be generally recommended.

The first dedicated multidisciplinary heart failure program in the United States was founded as the Division of Circulatory Physiology at the Columbia University College of Physicians & Surgeons in 1992. The Division was administratively and financially independent of the Division of Cardiology and grew to 24 faculty members at its peak. Its administrative innovations included (1) a comprehensive full-integrated service line, with 2 differentiated clinical teams, one devoted to drug therapy and the other to heart transplantation and ventricular assist devices; (2) a nurse specialist/physician assistant-led clinical service; and (3) a financial structure independent of (and not supported by) other cardiovascular medical or surgical services. The division had 3 overarching missions: (1) to promote a unique career development path for each faculty member to be linked to recognition in a specific area of heart failure expertise; (2) to change the trajectory and enhance the richness of intellectual discourse in the discipline of heart failure, so as to foster an understanding of fundamental mechanisms and to develop new therapeutics; and (3) to provide optimal medical care to patients and to promote the ability of other physicians to provide optimal care. The major research achievements of the division included (1) the development of beta-blockers for heart failure, from initial hemodynamic assessments to proof-of-concept studies to large-scale international trials; (2) the development and definitive assessment of flosequinan, amlodipine, and endothelin antagonists; (3) initial clinical trials and concerns with nesiritide; (4) large-scale trials evaluating dosing of angiotensin converting-enzyme inhibitors and the efficacy and safety of neprilysin inhibition; (5) identification of key mechanisms in heart failure, including neurohormonal activation, microcirculatory endothelial dysfunction, deficiencies in peripheral vasodilator pathways, noncardiac factors in driving dyspnea, and the first identification of subphenotypes of heart failure and a preserved ejection fraction; (6) the development of a volumetric approach to the assessment of myocardial shortening; (7) conceptualization and early studies of cardiac contractility modulation as a treatment for heart failure; (8) novel approaches to the identification of cardiac allograft rejection and new therapeutics to prevent allograft vasculopathy; and (9) demonstration of the effect of left ventricular assist devices to induce reverse remodeling, and the first randomized trial showing a survival benefit with ventricular assist devices. Above all, the division served as an exceptional incubator for a generation of leaders in the field of heart failure.

Radio frequency-based renal denervation is a safe and effective way of lowering blood pressure, a common condition associated with high cardiovascular risk. Several catheters have been developed to administer energy to the renal arteries and their side branches, thereby modulating sympathetic renal activity. The Symplicity Flex™ and Symplicity Spyral™ are first- and second-generation devices, respectively, for radio frequency-based renal denervation. There is a continuous need to further improve and adjust interventional antihypertensive therapies. Several randomized controlled trials have been conducted to investigate the safety and efficacy of these catheters and most were able to show radio frequency-based renal denervation to be feasible, safe and effective in lowering blood pressure in hypertensive patients with and without concomitant antihypertensive medication. Herein, the authors discuss the pathophysiologic concepts of renal denervation and its procedural approaches, report catheter designs, summarize clinical trials outcomes and, finally, discuss real-world evidence.

Resistant hypertension, defined as blood pressure that remains above goal despite using three or more antihypertensive medications, including a diuretic, affects a significant proportion of the hypertensive population and is associated with increased cardiovascular morbidity and mortality. Despite the availability of a wide range of pharmacological therapies, achieving optimal blood pressure control in patients with resistant hypertension remains a significant challenge. However, recent advances in the field have identified several promising treatment options, including spironolactone, mineralocorticoid receptor antagonists, and renal denervation. In addition, personalized management approaches based on genetic and other biomarkers may offer new opportunities to tailor therapy and improve outcomes. This review aims to provide an overview of the current state of knowledge regarding managing resistant hypertension, including the epidemiology, pathophysiology, and clinical implications of the condition, as well as the latest developments in therapeutic strategies and future prospects.

Arterial hypertension is a condition with a high prevalence in the global population and represents a major risk factor for adverse cardiovascular events, including stroke and death. Non-pharmacological and pharmacological interventions, with combination therapy as a standard strategy, are very effective in achieving optimal blood pressure (BP) goals. Nevertheless, in a non-negligible proportion of patients, drug therapy is ineffective at achieving BP targets or there is intolerance to specific anti-hypertensive medications. In this context, the use of invasive treatments for BP control, including renal denervation, represents a valuable therapeutic option. Renal denervation has experienced ups and downs over the years, with an initial growth period and a decline mainly linked to the initial negative results of a large, randomized trial. However, recent data from new trials and long-term follow-up of initial trials have confirmed the benefit and safety of the procedure by relaunching it in daily clinical practice. Additional research evaluating ablation methods other than radiofrequency are needed to be able to more clearly define the role of this procedure and the type of patients that can benefit most from it.

Growing evidence demonstrates the suitability of renal denervation in a broad population of patients; however, questions remain over its suitability and practical implementation. Given the rapidity of emerging data, this has been a challenging field for potential adopters to navigate. The purpose of this article is twofold: to provide navigation through emerging clinical data and evolving guidance; and to provide physicians with practical, evidence-based advice for identifying eligible patients and providing appropriate management in the pre- and postintervention settings. Although many of these recommendations are based on existing published guidance documents, we reflect equally on our own experiences of using this technology.

Hypertension remains a significant risk factor for major cardiovascular events worldwide. Poor adherence to treatment is extremely common in clinical practice, leading to uncontrolled hypertension. However, some patients with resistant hypertension still have uncontrolled blood pressure despite good medical compliance. A specific group of patients also develop adverse reactions to many blood pressure-lowering medications. These scenarios indicate that innovative strategies to lower blood pressure in challenging cases of hypertension are needed. The blood pressure-lowering efficacy of catheter-based renal denervation therapy to decrease sympathetic tone has been confirmed in many publications in recent years. Apart from both the invasiveness and the expensiveness of this technology, appropriate case selection to undergo this procedure is still developing. The utilization of renal denervation therapy for hypertension treatment in Thailand has lasted for 10 years with a good response in most cases. Currently, only certain interventionists at a few medical schools in Thailand can perform this procedure. However, more physicians are now interested in applying this technology to their patients. The Thai Hypertension Society Committee has reviewed updated information to provide principles for the appropriate utilization of renal denervation therapy. The blood pressure-lowering mechanism, efficacy, suitable patient selection, pre- and postprocedural assessment and procedural safety of renal denervation are included in this statement.

The aim of this study was to investigate alterations in the intrarenal blood pressure (BP) regulation system after renal denervation (RDN) guided by renal nerve stimulation (RNS). Twenty-one dogs were randomized to receive RDN at strong (SRA group, n = 7) or weak (WRA group, n = 7) BP-elevation response sites identified by RNS or underwent RNS only (RNS-control, RSC, n = 7). After 4 weeks of follow-up, renal sympathetic components, the main components of renin-angiotensin system (RAS) and the major transporters involved in sodium and water reabsorption were assessed by immunohistochemical analysis. Compared with RSC treatment, RDN therapy significantly reduced renal norepinephrine and tyrosine hydroxylase levels, decreased the renin content and inhibited the onsite generation of angiotensinogen. Moreover, the expression of exciting axis components, including angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II type-1 receptor, was downregulated, while protective axis components for the cardiovascular system, including ACE2 and Mas receptors, were upregulated in both WRA and SRA groups. Moreover, RDN reduced the abundance of aquaporin-1 and aquaporin-2 in kidneys. Although RDN had a minimal effect on overall NKCC2 expression, its activation (p-NKCC2) and directional enrichment in the apical membrane (mNKCC2) were dramatically blunted. All these changes were more obvious in the SRA group than WRA group. Selective RDN guided by RNS effectively reduced systemic BP by affecting the renal neurohormone system, as well as the sodium and water transporter system, and these effects at sites with a strong BP response were more superior.

Hypertension is a major health concern globally. Elevated blood pressure, initiated and maintained by the brain, is defined as neurogenic hypertension (NH), which accounts for nearly half of all hypertension cases. A significant increase in angiotensin II-mediated sympathetic nervous system activity within the brain is known to be the key driving force behind NH. Blood pressure control in NH has been demonstrated through intracerebrovascular injection of agents that reduce the sympathetic influence on cardiac functions. However, traditional antihypertensive agents lack effective brain permeation, making NH management extremely challenging. Therefore, developing strategies that allow brain-targeted delivery of antihypertensives at the therapeutic level is crucial. Targeting nanotherapeutics have become popular in delivering therapeutics to hard-to-reach regions of the body, including the brain. Despite the frequent use of nanotherapeutics in other pathological conditions such as cancer, their use in hypertension has received very little attention. This review discusses the underlying pathophysiology and current management strategies for NH, as well as the potential role of targeted therapeutics in improving current treatment strategies.

Given the unsatisfactory hypertension control rates and high rates of non-adherence to antihypertensive medications worldwide, device therapy which can safely provide durable blood pressure-lowering effects can fulfill the unmet need. A series of second-generation randomized sham-controlled renal denervation (RDN) trials have demonstrated the efficacy and safety of RDN in a wide range of hypertensive patients. The four representative consensus documents on RDN (from the Chinese Taiwan Hypertension Society and Taiwan Society of Cardiology [THS/TSOC 2019], Asia Renal Denervation Consortium 2019, European Society of Hypertension [ESH 2021], and Society for Cardiovascular Angiography & Intervention and National Kidney Foundation [SCAI/NKF 2021]) consistently recommend RDN as an alternative or complementary treatment strategy for patients with uncontrolled hypertension. In addition, both documents from Asia further recommend that RDN can be considered as an initial treatment strategy for drug-naïve hypertensive patients. There is still inconsistency regarding whether ambulatory blood pressure monitoring should be used routinely both before and after RDN, and whether patients with a secondary cause of hypertension could be treated with RDN if their blood pressure remains uncontrolled after definitive treatment (treatment-resistant secondary hypertension). The THS/TSOC consensus provides acronyms to summarize key aspects of patient selection (RDNi2) and pre-RDN assessments (RAS). The ESH and SCAI/NKF documents recommend establishing structured pathways for clinical practice and issues regarding reimbursement. All documents identify knowledge gaps in RDN, from identifying predictors of super-responders to demonstrating effects on cardiovascular events. These gaps should be urgently filled to facilitate the wider application of this device therapy for patients with hypertension.

Ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD) and is unfortunately without a cure. Current therapies focus on prevention of SCD, such as implantable cardioverter-defibrillator (ICD) implantation and anti-arrhythmic agents. Significant progress has been made in improving our understanding and ability to target the triggers of VF, via advanced mapping and ablation techniques, as well as with autonomic modulation. However, the critical substrate for VF maintenance remains incompletely defined. In this review, we discuss the evidence behind the basic mechanisms of VF and review the current role of catheter ablation in patients with VF.

Renal denervation (RDN) proved to significantly lower blood pressure (BP) at 2-6 months in patients on and off antihypertensive drugs. Given a lack of longer-term follow-up data, our aim was to assess the safety and efficacy of RDN up to five years taking into account antihypertensive drug regimen changes over time.

In the present single-center study, patients underwent RDN for (therapy resistant) hypertension. Patients underwent protocolized yearly follow-up out to five years. Data were collected on 24-h ambulatory BP and office BP monitoring, renal function, antihypertensive drug regimen, and safety events, including non-invasive renal artery imaging at 6/12 months. Efficacy analyses were performed using linear mixed-effects models.

Seventy-two patients with mean age 63.3 ± 9.5 (SD) years (51% female) were included. Median follow-up time was 3.5 years and Clark's Completeness Index was 72%. Baseline ambulatory daytime BP was 146.1/83.7 ± 17.4/12.2 mmHg under a mean number of 4.9 ± 2.7 defined daily doses (DDD). At five years, ambulatory daytime systolic BP as calculated from the mixed model was 120.8 (95% CI 114.2-127.5) mmHg and diastolic BP was 73.3 (95% CI 69.4-77.3) mmHg, implying a reduction of -20.9/-8.3 mmHg as compared to baseline estimates (p < 0.0001). The number of DDDs remained stable over time (p = 0.87). No procedure-related major adverse events resulting in long-term consequences were observed.

The BP-lowering effect of RDN was safely maintained at least five years post-procedure as reflected by a significant decrease in ambulatory daytime BP in the absence of escalating antihypertensive drug therapy over time.

While the blood pressure (BP)-lowering effect of renal denervation (RDN) has been established, long-term durability is a key prerequisite for a broader clinical implementation.

Our aims were to assess the long-term durability of the office BP (OBP)-lowering efficacy, antihypertensive medication (AHM) use, and safety of ultrasound RDN (uRDN).

Four weeks after withdrawal of AHM, patients with untreated daytime ambulatory BP ≥135/85 mmHg and <170/105 mmHg were randomised to uRDN (n=74) or sham (n=72) in the RADIANCE-HTN SOLO trial. Initiation of AHM was encouraged for home BP >135/85 mmHg following primary endpoint ascertainment at 2 months. Patients and physicians were unblinded at 6 months.  Results: Fifty-one of 74 patients (age: 53.9±11 years; 67% men) originally randomised to uRDN completed the 36-month follow-up. Initial screening OBP upon study entry was 145/92±14/10 mmHg on a mean of 1.2 AHM (range: 0-2.0). Baseline OBP after AHM washout was 154/99±13/8 mmHg. At 36 months, patients were on an average of 1.3 AHM (range: 0-3.0) with 8 patients on no AHM. OBP decreased by 18/11±15/9 mmHg from baseline to 36 months (p<0.001 for both). Overall, OBP control (<140/90 mmHg) improved from 29.4% at screening to 45.1% at 36 months (p=0.059). For patients uncontrolled at screening (n=36), systolic OBP decreased by 10.8 mmHg (p<0.001) at 36 months on similar AHM (p=0.158).

The safety and effectiveness of uRDN was durable to 36 months, with reduced OBP and improved OBP control despite a similar starting medication burden. No new uRDN-related long-term safety concerns were identified.