Renal DenervationRDN—Introduction

RDN aims to interrupt sympathetic nerve fibers that reside within and around the adventitia of the renal arteries. Both afferent (kidney-to-central nervous system) and efferent (central nervous system-to-kidney) sympathetic pathways are targeted. This dual pathway disruption is critical for the modulation of blood pressure and sympathetic activity [23].

RDN—Mechanistic Insights

Sympathetic overactivity plays a key role in the pathogenesis of hypertension by promoting the following four physiological effects: (1) increased renin secretion through β1-adrenergic stimulation at the juxtaglomerular apparatus, (2) enhanced sodium and water reabsorption through sympathetic activation of renal tubular transporters, (3) vasoconstriction of the renal vasculature increases systemic vascular resistance and impairs renal blood flow, (4) central nervous system excitation via renal afferent signaling further amplifies global sympathetic tone [24,25,26,27].

By ablating the renal nerves, RDN produces several beneficial physiological effects: Reduced plasma renin activity, leading to decreased angiotensin II and aldosterone production [24, 28]. Improved natriuresis and diuresis promote fluid and sodium excretion [25, 28]. Decreased systemic vascular resistance through loss of direct renal vasoconstrictor input [26, 28]. Attenuation of central sympathetic outflow, resulting in a reduction in global sympathetic nerve traffic [27].

To translate these physiological benefits into clinical practice, several technological approaches to RDN have emerged, each with distinct mechanisms, advantages, and limitations (Table 2). Radiofrequency (RF) ablation uses catheter-based thermal energy delivered point-by-point along the renal artery wall. RF ablation requires meticulous technique to achieve complete circumferential coverage and is operator-dependent [29,30,31]. Ultrasound-based ablation achieves circumferential nerve injury through a balloon-mounted ultrasound catheter, offering deeper and more uniform ablation in a single application, but carries potential risks such as thermal injury to adjacent structures and limited feasibility in small arteries [32, 33]. Chemical ablation, utilizing perivascular infusion of dehydrated alcohol, offers a minimally invasive method targeting adventitial nerves directly, although long-term safety and efficacy data remain limited. Key clinical trials are shown in Table 3. It is important to note that all trials excluded patients with GFR < 40 [29,30,31,32,33,34,35,36].

Table 3 RDN key clinical trialsRDN—Key Clinical Trials

Table 3 highlights the evolution and growing body of evidence supporting RDN as a therapeutic modality for hypertension. Early trials such as SYMPLICITY HTN-3 faced methodological challenges, including medication adherence, monitoring issues, and inexperienced operators [29]. While SYMPLICITY HTN-3 failed to demonstrate significant superiority over sham, subsequent studies with refined patient selection, improved blinding, and standardized procedural techniques such as SPYRAL HTN-OFF MED, RADIANCE-HTN SOLO, and RADIANCE II consistently showed statistically significant reductions in ambulatory and office blood pressure [34]. These trials also underscore the effectiveness of RDN both in the absence and presence of antihypertensive medications, as demonstrated by SPYRAL HTN-ON MED and RADIANCE-HTN TRIO [31, 32]. Notably, newer modalities such as ultrasound- and alcohol-based ablation have emerged with promising short-term efficacy, suggesting that both the technology and the target population are key determinants of procedural success. Collectively, these findings support a growing role for RDN in the management of hypertension, particularly in patients with resistant or uncontrolled disease.

RDN—Evidence from Meta-analyses and Long-Term Follow-Up

Recent meta-analyses have reaffirmed RDN’s efficacy in reducing BP across diverse populations with hypertension. A 2024 systematic review and meta-analysis including ten high-quality randomized sham-controlled trials (n = 2478) demonstrated that RDN reduced: 24-h ambulatory systolic BP by 4.4 mmHg (95% CI 2.7 to 6.1 mmHg; p < 0.00001), office systolic BP by 6.6 mmHg (95% CI 3.6 to 9.7 mmHg; p < 0.0001) compared with sham procedures [39]. Importantly, reductions in 24-h and office BP were observed regardless of the presence or absence of concomitant antihypertensive medications, suggesting a robust physiological effect of RDN independent of pharmacotherapy. Earlier meta-analyses had reported similar findings, with a 2021 analysis encompassing 11 sham-controlled trials showing a 24-h systolic BP reduction of approximately 4–5 mmHg [39]. Long-term follow-up data from the Global SYMPLICITY Registry further demonstrated sustained BP reductions (−17/ −8 mmHg office BP, −9/ −5 mmHg ambulatory BP) over 3 years [28]. Additionally, sensitivity analyses in the Vukadinović meta-analysis suggest that BP reductions after RDN are durable beyond 6 months, with ongoing reductions reported up to 3 years in trials such as SYMPLICITY HTN-3, SPYRAL HTN-ON MED, and RADIANCE-HTN SOLO [39].

RDN—Potential Cardiovascular Risk Reduction

Although trials evaluating major adverse cardiovascular events are ongoing, modeling studies predict that the magnitude of BP reduction achieved through RDN could translate into significant cardiovascular risk reduction. A meta-analysis of 344,000 participants found that a 5 mmHg reduction in systolic BP was associated with a 10% relative risk reduction in major cardiovascular events [40]. In another meta-analysis, over a mean follow-up of 3.26 years, antihypertensive therapy lowered the risk of the primary composite outcome (myocardial infarction, stroke, heart failure, or cardiovascular death) by 25%, all-cause mortality by 27%, heart failure by 38%, cardiovascular death by 43%, and the combined endpoint of the primary outcome or death by 22% [41]. Therefore, sustained BP reductions through RDN are likely to confer substantial long-term cardiovascular benefits, although dedicated outcome trials are required for definitive proof.

RDN—Limitations and Procedural Considerations

Potential procedural risks include rare instances of arterial dissection or stenosis, contrast-induced nephropathy in patients with pre-existing chronic kidney disease, and infrequent vascular access complications [36, 42]. Limitations of RDN encompass variability in blood pressure response between individuals, the ongoing requirement for antihypertensive therapy, and uncertainty regarding long-term efficacy. In some patients, minimal BP reduction is observed, likely attributable to anatomical or neurophysiological differences [43]. Procedural limitations, including vessel size, percentage of stenosis, accessory renal arteries, and atherosclerosis, are shown in Table 4. RDN alone may not normalize BP in all patients; it should be integrated with medical therapy rather than replaced [44]. While data up to 3 years support durable BP reductions, longer-term outcomes beyond 5 years are still under investigation [39].

Table 4 Anatomical inclusion and exclusion criteria in major RDN trialsRDN—Role in Comprehensive Hypertension Management

RDN is increasingly recognized as a potential adjunctive therapy within a comprehensive hypertension treatment strategy, particularly for RH. In the 2023 ESC/ESH guidelines, RDN is a Class IIb recommendation and may be considered in patients who: have uncontrolled hypertension despite the use of ≥ 3 antihypertensive medications, demonstrate intolerance to antihypertensive agents, are at high cardiovascular risk and require aggressive BP control, or prefer procedural intervention after shared decision-making [45]. A recent scientific statement on device-based therapies for hypertension made the following recommendations: (1) RDN is not currently recommended as routine therapy for hypertension management outside of clinical trial settings or specialized centers. (2) RDN may be considered in selected patients with: Persistent uncontrolled hypertension despite optimal pharmacologic therapy, documented medication non-adherence (after thorough evaluation), and/or severe intolerance to antihypertensive medications [37]. In 2025, the ACC/AHA guidelines assigned renal denervation a Class IIb recommendation, highlighting the importance of a multidisciplinary approach and shared decision-making with patients. The guidelines further specify that RDN may be considered for individuals with resistant hypertension despite optimal therapy or for those with uncontrolled hypertension who are unable to tolerate multiple medications [4].

RDN—Conclusion

In conclusion, RDN offers a physiologically targeted approach to blood pressure reduction by disrupting renal sympathetic pathways. Various techniques, including radiofrequency, ultrasound, and chemical ablation, have demonstrated consistent, albeit modest, antihypertensive effects across a spectrum of patient populations in randomized controlled trials. While RDN is not yet a first-line therapy, accumulating evidence supports its role as a safe and effective adjunctive strategy, particularly in patients with RH or medication intolerance.

Baroreceptor Activation TherapyBAT—Introduction

BAT is a novel device-based treatment for RH that delivers electrical stimulation to carotid sinus baroreceptors to modulate autonomic tone. By activating the baroreflex arc, BAT reduces sympathetic outflow and enhances parasympathetic activity, leading to lower systemic blood pressure [46]. It offers a non-pharmacologic option for patients unresponsive to optimized medical therapy. Understanding the underlying physiology is key to appreciating how BAT exerts its therapeutic effects.

Mechanistic Insights into BATBAT—Baroreceptor Function in Homeostasis

Baroreceptors, primarily located in the carotid sinus and aortic arch, are stretch-sensitive mechanoreceptors that continuously monitor blood pressure (BP) by sensing changes in arterial wall tension. Upon detection of increased BP, they generate afferent signals to the nucleus tractus solitarius (NTS) in the medulla oblongata. The NTS then modulates autonomic outputs to the heart and vasculature via two key mechanisms:

This baroreflex-mediated feedback loop is crucial for short-term BP regulation and buffering against fluctuations during physical or emotional stress.

BAT seeks to mimic this physiological mechanism through continuous low-intensity electrical stimulation of the carotid baroreceptors. This external stimulation exaggerates the natural baroreceptor signal, "tricking" the brain into perceiving high BP, which in turn leads to autonomic downregulation and BP reduction [47].

BAT—Modulation of the Sympathetic Nervous System

One of the primary pathophysiologic features of RH is chronic sympathetic nervous system (SNS) overactivity, which contributes to vasoconstriction, elevated heart rate, and sodium retention. BAT directly targets this dysregulation by suppressing sympathetic outflow and enhancing parasympathetic tone [47]. Mechanistically, BAT reduces muscle sympathetic nerve activity (MSNA) and renal sympathetic activity, both pivotal in systemic hypertension. BAT leads to vasodilation, reduced total peripheral resistance, and improved arterial compliance. Stabilizes baroreflex sensitivity, enhancing the system's responsiveness to pressure changes [48]. In long-term studies, BAT has shown sustained reductions in norepinephrine spillover, a biomarker of sympathetic activity, particularly in patients with severe or treatment-resistant hypertension [49].

BAT—Hemodynamic Effects

Chronic BAT therapy has demonstrated significant reductions in systolic and diastolic BP, as well as improvements in cardiac structure and function. Lohmeier and Iliescu illustrated that baroreflex activation leads to decreased left ventricular hypertrophy and improved arterial compliance, signifying systemic cardiovascular benefits [49].

BAT—Implantable Devices

BAT systems comprise an implantable pulse generator and leads positioned surgically along the carotid sinus. The device autonomously delivers electrical impulses at programmable intervals, optimized per patient to maintain therapeutic efficacy while minimizing adverse events. The currently available devices include:

Barostim neo™: FDA-approved for RH and HFrEF, this device improves upon the Rheos system with a less invasive implantation technique and enhanced safety profile.

Rheos® System: First-generation BAT device used in pivotal trials; although not commercially available, laid the foundation for modern BAT technologies.

BAT—Key Clinical Trial

The Rheos Pivotal Trial evaluated the efficacy and safety of BAT in patients with RH. This double-blind, randomized, placebo-controlled study involved 265 participants who had systolic blood pressure (SBP) ≥ 160 mmHg despite adherence to at least three antihypertensive medications, including a diuretic. The study was divided into two groups. Group A received immediate BAT for the first 6 months, and Group B had BAT initiation delayed until after the 6-month visit. Group A experienced a mean SBP reduction of 16 ± 29 mmHg. Group B had a mean SBP reduction of 9 ± 29 mmHg. The difference between the groups was not statistically significant (p = 0.08). At 12 months, both groups, having received BAT, showed a mean SBP reduction of approximately 25 mmHg from baseline. With regards to achieving SBP ≤ 140 mmHg, 42% of Group A reached this target compared to 24% of Group B (p = 0.005) at 6 months. At 12 months, over 50% of participants in both groups achieved SBP ≤ 140 mmHg after receiving BAT [50]. While the Rheos Pivotal Trial did not meet all its primary endpoints, particularly for acute response and procedural safety, it demonstrated that BAT could lead to significant and sustained reductions in SBP for patients with RH [51].

BAT—Clinical and Logistical Challenges

The implantation of BAT devices presents several procedural risks, including infection, hematoma, and potential cranial nerve injury. Although relatively rare, device-related complications such as lead displacement or battery failure require long-term surveillance and may necessitate periodic revisions. BAT is primarily indicated for patients with confirmed RH who have not achieved adequate control despite optimized pharmacologic therapy. Anatomical variations in the carotid sinus and the presence of concurrent cardiovascular comorbidities can influence device performance. The Rheos-Pivotal trial excluded patients with > 70% stenosis, prior carotid stent, and/or prior carotid endarterectomy [52]. While early and intermediate-term outcomes have been encouraging, real-world data on cost-effectiveness and broader applicability remain limited. Looking ahead, the development of closed-loop BAT systems, capable of real-time hemodynamic sensing and adaptive stimulation, offers the potential to enhance precision and individualization of therapy [53].

Endovascular and Other Emerging Interventions

Several novel interventional strategies are under active investigation for treatment-resistant hypertension, including hepatic denervation, multi-organ denervation, AV fistula creation, and cardiac neuromodulation (Table 5). Preclinical models have looked at combined renal and hepatic denervation, with no major hepatic or vascular complications, highlighting its feasibility and initial safety [54]. Building on success with RDN, the Spyral Gemini trial will look at the blood pressure-lowering effects of combined renal and epic denervation. Another emerging technique, cardiac neuromodulation, was evaluated in the MODERATO II trial using the BackBeat Moderato™ system—a pacemaker-based device that adjusts atrioventricular intervals to modulate autonomic tone. Among patients with an existing pacing indication, this approach yielded a ~ 12 mmHg systolic BP reduction over six months without adverse cardiac events [55].

Table 5 Trials of emerging interventions

Adjunctive neuromodulatory therapies are also being explored. Carotid body modulation targets peripheral chemoreceptor hyperactivity, which contributes to sympathetic overdrive in hypertension. The CALM-FIM study demonstrated the safety and short-term efficacy of unilateral carotid body ablation in lowering blood pressure, and the ongoing CALM-2 trial will evaluate the MobiusHD implant in a double-blind, sham-controlled design with 5-year follow-up [52]. This modality may be particularly beneficial in patients with heightened sympathetic tone or comorbid obstructive sleep apnea.

Arteriovenous fistula (AVF) therapy, involving central shunt creation (e.g., iliac artery to vein), has shown promising BP reductions (office: 25 mmHg and 24H ambulatory 13 mmHg at 12 months) via reduced systemic vascular resistance, as evidenced by the ROX CONTROL HTN trial. However, concerns such as venous stenosis and volume overload necessitate close hemodynamic monitoring [56, 57]. Collectively, these findings suggest promising directions for future autonomic-targeted therapies in hypertension management.