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Hypertension remains a leading global health challenge, affecting over 1.3 billion individuals worldwide and contributing significantly to cardiovascular morbidity and mortality. In recent years, interventional device-based therapies have emerged as promising adjuncts by targeting sympathetic overactivity and autonomic dysregulation, key mechanisms in the pathogenesis of hypertension. Currently, the use of these interventional therapies is primarily reserved for patients with resistant hypertension (RH) who remain uncontrolled despite optimal medical therapy. This review provides an overview of the evolving landscape of interventional approaches, including renal denervation (RDN), baroreceptor activation therapy (BAT), carotid body modulation, hepatic denervation, and cardiac neuromodulation. Among these, RDN has the most robust clinical trial evidence, while other neuromodulatory strategies are being evaluated in early-phase studies. Additionally, this review underscores the importance of systematically identifying and managing secondary causes of hypertension, such as primary aldosteronism, renovascular disease, and obstructive sleep apnea, before considering procedural interventions. As the field advances, these therapies may assume a more prominent role in precision-based hypertension management.
Key Summary Points
Interventional therapies are emerging as promising options for resistant hypertension (RH), with renal denervation (RDN) demonstrating the most consistent blood pressure reductions in randomized sham-controlled trials across diverse populations.
Baroreceptor activation therapy, hepatic denervation, and cardiac neuromodulation offer alternative neuromodulatory strategies targeting autonomic dysfunction, with early trials showing significant reductions in systolic blood pressure and favorable safety profiles.
Secondary hypertension must be carefully ruled out before considering device-based interventions, with primary aldosteronism, renovascular hypertension, and obstructive sleep apnea being the most common reversible causes.
Non-adherence to pharmacologic therapy remains a major contributor to uncontrolled blood pressure, and team-based care, simplified regimens, and telemonitoring should be optimized before escalating to invasive therapies.
Future directions include head-to-head trials, long-term outcome data, and integration with digital health tools, which will be essential for defining the role of interventional therapies in personalized hypertension management.
Introduction
Hypertension represents a major global health burden, affecting approximately 1.39 billion people globally in 2010, with the number of people aged 30–79 diagnosed with the condition doubling from 1990 to 2019 [1, 2]. Globally, for men and women, treatment rates were only 38% and 47%, with blood pressure control achieved in just 23% and 18%, respectively. This challenge is amplified in low- and middle-income countries (LMICs), which often exhibit higher hypertension rates alongside lower levels of awareness and control [1]. Factors contributing to hypertension are diverse, including high sodium intake, low potassium intake, physical inactivity, and obesity.
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The American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology/European Society of Hypertension (ESC/ESH) provide comprehensive guidelines for the management of hypertension, shown in Table 1 [3, 4]. Accurate diagnosis is important for management and can be complicated by phenomena such as improper technique and white coat hypertension, with studies showing increased cardiovascular risk in the latter disease phenotype [5].
Table 1
ACC/AHA and ESC/ESH guidelines
Classification
ACC/AHA 2025 (mmHg)
ESC/ESH 2023 (mmHg)
Threshold for hypertension
≥ 130/ ≥ 80
≥ 140/ ≥ 90
Normal blood pressure ranges (mmHg)
Normal: < 120/80
Elevated: 120–129/ < 80
Optimal: < 120/80
Normal: 120–129/80–84
High-normal: 130–139/85–89
Hypertension—Stage 1/Grade 1
130–139/80–89
140–159/90–99
Hypertension—Stage 2/Grade 2
≥ 140/90
160–179/100–109
Hypertension—Stage 3/Grade 3
Not defined separately
≥ 180/110
This table summarizes the ACC/AHA and ESC/ESH definitions of hypertension and hypertension staging/grading
ACC/AHA American College of Cardiology/American Heart Association. ESC/ESH European Society of Cardiology/European Society of Hypertension
Pharmacologic therapy, while effective, faces challenges such as adverse effects and tolerability, adherence issues, cost and accessibility, and resistant hypertension (RH) [6‐8]. Non-adherence, in part, is caused by drug intolerance due to well-described side effects, including hypo- and hyperkalemia, hyponatremia, hypotension, cough, dizziness, lower extremity edema, and headache, demonstrating the need for hypertensive medications to be efficacious and highly tolerable [6]. Interventional approaches, including renal denervation (RDN), baroreceptor activation therapy (BAT), carotid body modulation, and hepatic denervation, have emerged as potential solutions to these challenges [9]. These techniques are not widely used and not currently recommended for standard care; however, they have demonstrated promise for the treatment of RH in some clinical trials.
The purpose of this review is to summarize clinical trial evidence for interventional hypertension therapies, highlighting their potential role in improving blood pressure control and addressing the limitations of current pharmacologic treatments. Additionally, we discuss the workup for patients with RH, as current guidelines support optimal medical therapy prior to interventional approaches.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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Rationale for Interventional Approaches
Resistant Hypertension
RH is defined as a blood pressure that remains above target despite adherence to three antihypertensive agents at their maximally tolerated dose and appropriate frequency. This generally includes a diuretic, long-acting calcium channel blocker, and a renin–angiotensin system blocker. Prevalence is approximately 18% of patients [7].
Patients with RH may benefit from a thorough evaluation and targeted management of potential secondary causes (Fig. 1). Distinguishing true RH from pseudo-resistance caused by factors such as suboptimal dosing, poor adherence, or white coat effect is essential. Both European and American guidelines recommend confirming true RH through a comprehensive evaluation to identify secondary causes [10]. See the corresponding reference for a thorough review of each condition below [11].
Fig. 1
A proposed evaluation algorithm for resistant hypertension, highlighting the prevalence and initial testing for secondary causes based on the 2018 American Heart Association Scientific Statement and 2023 European Society of Hypertension Guidelines. CT computed tomography, TSH thyroid-stimulating hormone
Primary aldosteronism (PA) is a leading cause of secondary and RH, with prevalence estimates ranging from 3.2% to 12.7% in primary care and up to 30% in referral centers [9]. It results from autonomous aldosterone secretion, most commonly due to bilateral adrenal hyperplasia or a unilateral adenoma. Initial screening with the aldosterone-to-renin ratio (ARR) should be performed after correcting hypokalemia and adjusting interfering medications (i.e., mineralocorticoid receptor antagonists, MRAs) [12]. Patients with an ARR > 20, elevated plasma aldosterone (> 10 ng/dl), and suppressed renin (PRA < 1 ng/ml/h or DRC < 10 pg/ml) are considered to have a positive screen for PA [13, 14].
Pheochromocytoma
Pheochromocytoma, though rare (< 0.6% of patients with hypertension), should be suspected in those with episodic hypertension, headache, palpitations, and sweating [4]. Diagnosis relies on plasma or urinary metanephrines, followed by imaging to localize the tumor [14].
Obstructive Sleep Apnea
Obstructive sleep apnea is highly prevalent in RH and contributes to masked and nocturnal hypertension [15]. Clinical suspicion should prompt a sleep study referral. Treatment with CPAP can yield modest improvements in BP of approximately 6–7 mmHg [14].
Renovascular Hypertension
Renovascular hypertension is caused by narrowing of the renal arteries, leading to reduced renal perfusion and activation of the renin–angiotensin system. Atherosclerotic renal artery disease (ARVD) accounts for most cases, whereas fibromuscular dysplasia (FMD) typically affects younger, otherwise healthy women [16, 17].
Other Causes: Cushing’s Syndrome, Thyroid Disorders, Coarctation of the Aorta
Several uncommon but clinically relevant causes of secondary hypertension include Cushing’s syndrome, thyroid dysfunction, and coarctation of the aorta, each accounting for < 1% of cases [17, 18].
Pharmacologic Management
Once secondary causes are excluded, the patient is considered to have RH when adherent to maximally tolerated doses of three complementary antihypertensive agents: a long-acting calcium channel blocker, a renin–angiotensin system blocker (ACE inhibitor or ARB), and a diuretic [17]. If blood pressure remains above goal, MRAs are the preferred fourth-line therapy based on results of the Pathway-2 trial [19].
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Non-pharmacologic Solutions: Addressing Medication Non-adherence and Treatment Resistance
Non-adherence is a major contributor to apparent treatment resistance, with up to 25% of patients failing to fill their initial antihypertensive prescriptions [17, 20]. To improve adherence and outcomes, team-based care has proven effective, with nonphysician-led interventions reducing systolic BP by over 7 mmHg [21]. Telehealth approaches, including self-monitoring and clinician-guided titration, as demonstrated in the TASMINH4 trial, further enhance BP control. These scalable strategies should be integrated into hypertension care to optimize treatment success before considering invasive interventions [22].
Clinical Trials for Interventional Hypertension Therapies
Renal Denervation
RDN—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 [24‐27].
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 [29‐31]. 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 [29‐36].
Infuses dehydrated alcohol into perivascular space to chemically destroy renal sympathetic nerves
Peregrine™ System Infusion Catheter
Potentially more complete adventitial nerve targeting
Minimally invasive catheter design
Short procedure time
Risk of alcohol leakage
Limited long-term data
Still investigational in broader populations
RDN has evolved with the development of multiple delivery modalities aimed at optimizing sympathetic nerve disruption while minimizing vascular injury. This table summarizes the major techniques used for RDN, highlighting their mechanisms, advantages, and limitations
This table summarizes key clinical trials evaluating RDN for blood pressure (BP) reduction across different patient populations and technologies
RDN renal denervation, BP blood pressure, RF radiofrequency, RF RDN radiofrequency-based renal denervation, RFM radiofrequency ablation in the main renal artery only, RFB radiofrequency ablation in the main, side branch, and accessory renal arteries, USM ultrasound-based ablation in the main renal artery, RH resistant hypertension
RDN—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 trials
Anatomical inclusion and exclusion criteria in major RDN trials. This table summarizes the anatomical eligibility requirements across pivotal RDN trials
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 Therapy
BAT—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 BAT
BAT—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:
Inhibition of sympathetic outflow.
Activation of parasympathetic (vagal) tone.
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].
Nitinol arteriovenous coupler placed between the common iliac artery and vein aimed to shunt arterial blood to the vein
Durable BP reduction of 25 mmHg in the office and 13 mmHg in ambulatory BP
NCT02895386
Summary of Emerging Interventional Therapies for Hypertension and Autonomic Modulation. This table highlights prospective clinical trials evaluating novel device-based interventions targeting autonomic regulation and vascular remodeling in patients with hypertension or high cardiovascular risk. BP blood pressure; T2DM type II diabetes mellitus; SBP systolic blood pressure, DC-PPM dual chamber permanent pacemaker, RH resistant hypertension
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.
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Future Perspectives and Challenges
While early data from these emerging interventions are promising, several challenges remain. Patient-specific anatomy, procedural complexity, and operator experience may limit widespread applicability. Long-term efficacy remains unknown. Nerve regrowth, vascular remodeling, and physiologic compensation could diminish the initial BP-lowering effects. Currently, there is a lack of head-to-head randomized trials comparing these novel approaches to RDN, intensive medical therapy, and each other. Determining the optimal patient phenotype for each intervention (e.g., isolated systolic hypertension, obesity-related hypertension) will be crucial. As evidence accumulates, future consensus documents and clinical guidelines will be essential to define standardized thresholds for patient selection, sequencing of interventional modalities, and post-procedural management protocols that can be safely and effectively integrated into routine hypertension care.
With rising healthcare costs across the world, cost-effectiveness is critical to the implementation and utility of new therapies. Recent cost-utility models have strengthened the economic case for endovascular ultrasound RDN with a goal to be cost-effective, considered to be less than $50–100,000/quality-adjusted life years (QALY). A U.S.-based Markov model using RADIANCE‑HTN TRIO data yielded an incremental cost-effectiveness ratio (ICER) of approximately $12,900/(QALY), assuming a procedural cost around $23,000 and an SBP reduction of 8.5 mmHg [58]. The same model used in European countries has also demonstrated similar cost-effectiveness with ICERs between €1654 and €6261/QALY—well within their health-system willingness-to-pay thresholds of €20,000 to €50,000/QALY [59]. By contrast, baroreflex activation therapy (BAT) remains economically unquantified in RH. Available modeling in heart failure populations suggests marginal acceptability (ICER ~ €50,000–60,000/QALY). No published cost-effectiveness models yet exist for other modalities (hepatic denervation, cardiac neuromodulation for RH, carotid body modulation, or arteriovenous fistula therapy), highlighting a key gap.
Reimbursement, regulatory approval pathways, and payer frameworks must adapt to accommodate procedure-based therapies for hypertension, particularly in health systems where pharmacologic management remains the default standard. As these interventional technologies evolve, integration with remote monitoring platforms, AI-driven patient stratification, and cost-effectiveness modeling will be crucial for optimizing clinical outcomes and guiding reimbursement decisions.
Conclusions
As hypertension continues to pose a significant global health burden, interventional therapies are reshaping the treatment landscape, particularly for patients with resistant or treatment-intolerant hypertension. Among these, RDN has the most robust clinical trial evidence, with recent sham-controlled studies consistently demonstrating meaningful reductions in both office and ambulatory blood pressure across diverse populations. While these reductions in blood pressure may translate to a 10% risk reduction, more outcome data are needed from ongoing trials. As digital health and artificial intelligence tools evolve, their integration with interventional strategies may optimize patient selection, procedural timing, and longitudinal monitoring, ultimately improving blood pressure control and reducing cardiovascular risk on a global scale.
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Declarations
Conflict of Interest
Vicki Groo, Vanessa Rowe – Medtronic – Consulting. Jeffrey D. Taylor, Adhir Shroff, Chukwunonyelum Uche, Aleyah Hattab, and Arvind Draffen have nothing to disclose.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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