Reframing renal denervation: from blood pressure reduction to autonomic disease modification—a state-of-the-art review

Abstract

Background

Renal denervation (RDN) has re-emerged as an evidence-based treatment for uncontrolled and resistant hypertension following consistent findings from contemporary sham-controlled randomized trials. Because renal sympathetic signaling plays a central role in cardiovascular (CV), renal, and metabolic homeostasis, the therapeutic effects of RDN may extend beyond blood pressure (BP) reduction. This review reframes RDN within a precision autonomic medicine framework by integrating contemporary mechanistic evidence, phenotype-guided patient selection, and future directions for outcome-oriented clinical trials.

Methods

A comprehensive literature search was conducted in PubMed/MEDLINE for studies published between January 2009 and 30 June 2026. Randomized controlled trials, observational studies, mechanistic investigations, systematic reviews, consensus statements, and major international guidelines evaluating the mechanisms, clinical effects, procedural aspects, and emerging applications of RDN were reviewed. Evidence was synthesized narratively with emphasis on autonomic modulation, target-organ protection, precision phenotyping, and future trial design.

Results

Contemporary evidence demonstrates that RDN provides durable reductions in ambulatory BP with an acceptable long-term safety profile. Experimental and clinical studies further suggest favorable effects on sympathetic activity, neurohumoral activation, inflammation, oxidative stress, endothelial function, and cardiac, renal, and metabolic remodeling. We propose an autonomic responder phenotype integrating ambulatory BP characteristics, autonomic biomarkers, target-organ involvement, and anatomical suitability to facilitate precision-guided patient selection. We also outline a framework for phenotype-enriched clinical trials incorporating standardized procedural verification and clinically meaningful CV and renal outcomes beyond BP reduction. However, evidence supporting autonomic disease modification remains preliminary, with most studies relying on surrogate endpoints.

Conclusions

RDN is an established therapy for appropriately selected patients with hypertension, whereas its broader role as a precision-guided autonomic disease-modifying intervention remains investigational. Future progress requires validated responder phenotypes, objective confirmation of successful denervation, standardized procedural methodologies, and adequately powered randomized outcome trials.

Graphical Abstract

INTRODUCTION

Hypertension remains the leading modifiable risk factor for cardiovascular (CV) morbidity and mortality worldwide despite the availability of effective pharmacological therapies and lifestyle interventions. Although substantial advances have been achieved in antihypertensive treatment over recent decades, blood pressure (BP) control remains suboptimal in routine clinical practice, leaving millions of patients at increased risk of myocardial infarction, stroke, heart failure (HF), chronic kidney disease (CKD), and premature death [1,2,3]. This persistent gap between therapeutic efficacy and real-world BP control has renewed interest in device-based therapies, among which catheter-based renal denervation (RDN) has emerged as the most extensively investigated and clinically validated intervention. Contemporary sham-controlled randomized trials have consistently demonstrated that RDN produces durable reductions in both office and ambulatory BP, leading to its re-establishment as an evidence-based adjunctive therapy for appropriately selected patients with hypertension [2,3].

The biological rationale for RDN is rooted in the central role of the sympathetic nervous system (SNS) in CV and renal homeostasis. Renal sympathetic efferent fibers regulate renin secretion, tubular sodium reabsorption, and renal vascular resistance, whereas renal afferent nerves transmit signals that influence central sympathetic outflow. Persistent sympathetic activation contributes not only to hypertension but also to adverse cardiac remodeling, atrial and ventricular arrhythmogenesis, HF progression, CKD, metabolic dysfunction, systemic inflammation, oxidative stress, and endothelial injury. Consequently, renal sympathetic signaling represents an attractive therapeutic target extending far beyond conventional BP regulation [4,5,6,7].

In a recent review, we comprehensively reviewed RDN from the perspective of patient selection, emphasizing the clinical, physiological, and anatomical determinants associated with successful BP reduction and proposing a precision-based framework to optimize patient selection for RDN [8]. That review addressed one of the most important unresolved questions in the contemporary RDN field—who is most likely to benefit from RDN. While this patient-centered perspective represented an important step toward precision hypertension management, it primarily evaluated RDN as an antihypertensive intervention with BP reduction as the principal therapeutic objective.

The present review addresses a fundamentally different, yet complementary, question: should RDN be regarded solely as a BP-lowering procedure, or does it function as an autonomic disease-modifying therapycapable of modifying the biological mechanisms underlying CV, renal, and metabolic disease progression? Rather than focusing primarily on predictors of antihypertensive response, we synthesize emerging mechanistic, translational, and clinical evidence demonstrating that interruption of renal sympathetic signaling modulates neurohumoral activation, inflammation, oxidative stress, endothelial dysfunction, target-organ remodeling, and cardiometabolic homeostasis [5,6,7,9]. Furthermore, we extend the precision medicine paradigm by proposing the concept of an autonomic responder phenotype, integrating autonomic biomarkers, physiological measurements, target-organ characteristics, and procedural factors to guide patient selection beyond conventional BP-based criteria. Accordingly, whereas our previous review focused on who should undergo RDN, the present review focuses on why RDN may exert biological effects beyond BP lowering and how these mechanisms may support precision autonomic medicine across multiple CV, renal, and metabolic disorders.

Importantly, accumulating experimental and clinical evidence suggests that the biological consequences of RDN may not be adequately captured by BP reduction alone. By interrupting both afferent and efferent renal neural signaling, RDN exerts systemic sympathoinhibitory effects that influence multiple CV and renal pathways. Preclinical investigations have demonstrated attenuation of central sympathetic activity, reduced neurohumoral activation, improvement in cardiac remodeling, mitigation of renal injury, and favorable effects on inflammatory and metabolic pathways following renal nerve ablation [5,6,7,9]. Emerging clinical observations further suggest potential therapeutic benefits in conditions characterized by heightened sympathetic activation, including atrial fibrillation (AF), HF, CKD, obstructive sleep apnea (OSA), and metabolic dysfunction [10,11,12,13].

These observations challenge the traditional perception of RDN as merely a BP-lowering procedure. Instead, they support a broader conceptual framework in which RDN may function as a platform for autonomic disease modification. Within this perspective, BP reduction represents only one measurable manifestation of a more comprehensive biological effect mediated through restoration of autonomic homeostasis and attenuation of sympathetic overactivity.

In this state-of-the-art review, we critically evaluate the emerging concept of RDN as an autonomic disease-modifying therapy. Specifically, we (i) summarize the biological basis of renal sympathetic signaling and its systemic consequences, (ii) integrate contemporary mechanistic and clinical evidence supporting disease modification beyond BP reduction, (iii) propose an autonomic responder phenotype to advance precision patient selection, and (iv) discuss future directions for biomarker-guided therapy and outcome-oriented clinical trial design. By extending the current literature beyond patient selection and antihypertensive efficacy, this review provides a comprehensive conceptual framework for the evolving role of RDN in precision CV medicine.

METHODS

Literature search strategy

A comprehensive narrative literature review was conducted to evaluate the biological and clinical effects of RDN beyond BP reduction. Electronic searches were performed in PubMed, Embase, and Scopus to identify relevant studies published between January 2009 and June 30, 2026, corresponding to the modern era of catheter-based RDN. The final literature search was completed on June 30, 2026.

The search strategy combined Medical Subject Headings (MeSH) and free-text keywords, including “renal denervation,” “renal sympathetic nerves,” “sympathetic nervous system,” “autonomic dysfunction,” “autonomic modulation,” “resistant hypertension,” “heart failure,” “atrial fibrillation,” “chronic kidney disease,” “cardiac remodeling,” “metabolic syndrome,” “precision medicine,” “autonomic biomarkers,” and “cardiovascular outcomes.” Additional relevant studies were identified through manual screening of the reference lists of eligible articles and contemporary review papers.

Original investigations, randomized controlled trials, sham-controlled trials, observational studies, mechanistic and translational investigations, systematic reviews, meta-analyses, expert consensus statements, and major review articles published in English were considered eligible. Preference was given to contemporary studies evaluating autonomic mechanisms, sympathetic modulation, target-organ effects, and clinical outcomes extending beyond conventional BP reduction. Conference abstracts, duplicate publications, non-English articles, and studies lacking sufficient methodological quality or direct relevance to autonomic mechanisms were excluded.

Given the evolving and multidisciplinary nature of this field, a narrative review methodology was intentionally adopted to integrate evidence from basic science, translational research, physiology, interventional cardiology, nephrology, hypertension, and CV medicine [14]. The primary objective was not to perform a quantitative evidence synthesis but to critically evaluate whether the accumulated mechanistic and clinical evidence supports a conceptual shift in the understanding of RDN from a BP-lowering intervention toward an autonomic disease-modifying therapy.

WHY BP MAY BE AN INCOMPLETE ENDPOINT

BP reduction has historically served as the primary therapeutic target and efficacy endpoint in hypertension management. Consequently, the development and clinical evaluation of RDN have largely been centered on its ability to lower office, home, and ambulatory BP measurements [1,2]. While BP reduction remains clinically meaningful, growing evidence suggests that this hemodynamic parameter alone may not fully capture the biological and therapeutic effects of RDN.

Hypertension is increasingly recognized as a multifaceted systemic disorder characterized by complex interactions among neurohumoral activation, vascular dysfunction, inflammation, oxidative stress, and target-organ damage [4]. Within this network, SNS overactivity plays a pivotal role not only in elevating BP but also in driving adverse CV and renal remodeling. Excessive sympathetic activation contributes to left ventricular hypertrophy (LVH), myocardial fibrosis, endothelial dysfunction, arterial stiffness, chronic kidney injury, and metabolic dysregulation, many of which may progress independently of BP levels [4,5,6].

The limitations of relying solely on BP as a surrogate endpoint are increasingly recognized. By interrupting both afferent and efferent renal sympathetic pathways, RDN influences multiple neurohumoral mechanisms involved in CV homeostasis and disease progression [5]. Experimental studies have demonstrated reductions in central sympathetic outflow, attenuation of renin–angiotensin–aldosterone system (RAAS) activation, decreased oxidative stress, and modulation of inflammatory signaling following renal nerve ablation [5]. These biological effects have the potential to influence CV and renal structure and function independently of systemic BP changes.

Clinical observations further support this perspective. Improvements in left ventricular mass, diastolic function, atrial remodeling, arrhythmia burden, and markers of renal injury have been reported following RDN, in some cases appearing disproportionate to the degree of BP reduction achieved [3,5,10]. Although definitive outcome trials remain limited, these findings suggest that sympathetic modulation may exert broader therapeutic effects extending beyond hemodynamic control alone.

The substantial heterogeneity of BP response observed after RDN also challenges a purely BP-centered paradigm. Some patients exhibit only modest reductions in BP despite technically successful procedures and evidence of sympathetic modulation [2]. If BP reduction is regarded as the sole marker of treatment success, such individuals may be classified as non-responders. However, this definition may overlook clinically meaningful effects on autonomic regulation, target-organ injury, and disease progression.

Collectively, these observations indicate that BP reduction may represent only one dimension of the therapeutic impact of RDN. A broader framework is therefore required—one that recognizes chronic autonomic dysregulation as a fundamental driver of CV and renal disease and considers the possibility that RDN may modify these pathological processes through mechanisms extending beyond conventional BP lowering.

RENAL SYMPATHETIC SIGNALING AND SYSTEMIC AUTONOMIC REGULATION

The kidney occupies a unique position within the autonomic nervous system, functioning not only as a target of sympathetic regulation but also as an active modulator of systemic autonomic homeostasis. Through a complex network of afferent and efferent neural pathways, the kidneys communicate bidirectionally with central autonomic centers, thereby influencing CV, renal, and metabolic function [4,6].

Renal efferent sympathetic nerves originate from central autonomic nuclei and innervate the renal vasculature, tubules, and juxtaglomerular apparatus. Increased efferent sympathetic activity promotes renin release, enhances sodium and water reabsorption, reduces renal blood flow, and increases renal vascular resistance, all of which contribute to BP elevation and CV stress [4]. Chronic activation of these pathways further amplifies neurohormonal signaling through interactions with the RAAS, creating a self-perpetuating cycle of sympathetic excitation and CV injury [4].

Equally important are the renal afferent sensory nerves, which transmit signals from the kidney to the central nervous system (CNS). Under physiological conditions, these neural pathways contribute to normal autonomic regulation. However, in pathological states such as hypertension, CKD, obesity, and HF, renal afferent signaling becomes exaggerated, promoting sustained activation of central sympathetic networks [6]. Experimental studies have demonstrated that renal injury and ischemia can trigger afferent neural activity that increases sympathetic outflow to multiple organ systems, extending the impact of renal dysfunction far beyond the kidney itself [6].

This bidirectional interaction has led to the concept of the reno-central autonomic axis, whereby pathological renal signaling contributes to generalized sympathetic overactivity throughout the CV system [5,6]. Excessive sympathetic activation has profound biological consequences extending well beyond BP regulation. Within the myocardium, chronic adrenergic stimulation promotes LVH, myocardial fibrosis, impaired diastolic function, and electrical remodeling. These processes contribute to the development and progression of HF and AF, 2 conditions strongly associated with autonomic imbalance [5,10].

At the vascular level, sympathetic overactivity contributes to endothelial dysfunction, increased arterial stiffness, oxidative stress, and vascular inflammation. These changes accelerate vascular aging and promote the development of atherosclerotic and hypertensive target-organ damage [5]. Simultaneously, persistent sympathetic stimulation within the kidney exacerbates glomerular hypertension, renal fibrosis, and progressive nephron loss, establishing a vicious cycle in which renal dysfunction further amplifies autonomic dysregulation [4].

Beyond the CV and renal systems, increasing evidence suggests that sympathetic signaling plays an important role in metabolic homeostasis. Elevated sympathetic activity has been linked to insulin resistance, adipose tissue dysfunction, chronic low-grade inflammation, and metabolic syndrome, highlighting the systemic consequences of autonomic imbalance [5]. These observations support the concept that sympathetic overactivity represents a shared pathophysiological mechanism underlying multiple chronic diseases.

Within this framework, RDN should not be viewed merely as a localized intervention targeting renal nerves to lower BP. By disrupting both afferent and efferent renal neural pathways, RDN has the potential to attenuate central sympathetic activation and modify pathological processes across several organ systems [5]. This broader understanding provides the mechanistic foundation for considering RDN as a potential autonomic disease-modifying therapy rather than solely an antihypertensive procedure.

Accordingly, the therapeutic significance of RDN may lie in its capacity to interrupt maladaptive autonomic signaling at a critical interface connecting the kidney, CV system, and CNS. This broader mechanistic framework provides a biological basis for the concept of RDN as an autonomic disease-modifying therapy (Fig. 1).

Fig. 1. Conceptual framework of RDN as an autonomic disease-modifying therapy. RDN interrupts both afferent and efferent renal sympathetic signaling, resulting in attenuation of central sympathetic outflow and downstream neurohumoral activation. Through modulation of autonomic pathways, RDN may influence multiple biological mechanisms, including renin–angiotensin–aldosterone system activation, inflammation, oxidative stress, endothelial dysfunction, and target-organ remodeling. These effects may contribute to disease modification across a spectrum of cardiovascular, renal, and metabolic disorders extending beyond hypertension.

RDN, renal denervation.

MECHANISMS OF DISEASE MODIFICATION BEYOND BP REDUCTION

The concept of RDN as an autonomic disease-modifying therapy is founded on the premise that SNS modulation exerts biological effects extending beyond hemodynamic control. While BP reduction remains the most visible clinical consequence of RDN, accumulating evidence suggests that interruption of renal sympathetic signaling influences multiple pathophysiological pathways involved in CV, renal, and metabolic disease progression [5,15].

Neurohumoral modulation

One of the principal consequences of sympathetic overactivity is persistent activation of neurohumoral systems, particularly the RAAS. Through stimulation of juxtaglomerular cells, renal sympathetic nerves promote renin release and subsequent activation of downstream hormonal cascades that contribute to vasoconstriction, sodium retention, vascular remodeling, and myocardial fibrosis [5]. By disrupting both afferent and efferent renal neural pathways, RDN attenuates sympathetic drive and may reduce maladaptive neurohumoral activation, thereby influencing disease processes beyond arterial pressure regulation [5,15].

Inflammation and immune regulation

Chronic low-grade inflammation has emerged as a key contributor to hypertension and CV disease. Sympathetic activation influences immune cell trafficking, cytokine production, and inflammatory signaling pathways that participate in vascular injury and end-organ damage. Experimental studies have demonstrated reductions in pro-inflammatory mediators following RDN, suggesting a potential interaction between autonomic modulation and immune regulation [5]. Although the clinical implications of these findings remain incompletely defined, suppression of inflammatory activity may contribute to the broader CV effects observed after RDN.

Oxidative stress and endothelial function

Excessive sympathetic stimulation is associated with increased oxidative stress and impaired endothelial function, both of which play central roles in vascular disease progression. Elevated catecholamine levels promote reactive oxygen species generation, reduce nitric oxide bioavailability, and accelerate vascular dysfunction [7]. Several experimental investigations have suggested that RDN may improve endothelial homeostasis and reduce oxidative stress, thereby contributing to favorable vascular remodeling independent of BP reduction [5,7].

Cardiac remodeling

Sympathetic overactivity is a major driver of structural and functional cardiac remodeling. Persistent adrenergic stimulation promotes LVH, myocardial fibrosis, impaired ventricular relaxation, and electrical instability [10,16]. These pathological changes contribute to the development of HF and AF while increasing overall CV risk. Emerging evidence suggests that RDN may facilitate reverse remodeling through attenuation of sympathetic signaling, resulting in reductions in left ventricular mass and improvements in diastolic function that may not be entirely explained by reductions in BP alone [10,16].

Renal protection

The kidney is both a source and a target of sympathetic activation. Increased renal sympathetic tone contributes to renal vasoconstriction, glomerular hypertension, sodium retention, and progressive nephron injury [4]. By interrupting pathological neural signaling, RDN may mitigate mechanisms involved in CKD progression. Experimental and early clinical studies suggest favorable effects on renal hemodynamics and markers of renal injury, supporting the hypothesis that autonomic modulation may provide renoprotective benefits beyond BP control [17].

Metabolic effects

Increasing attention has focused on the relationship between sympathetic overactivity and metabolic dysfunction. Elevated sympathetic activity has been associated with insulin resistance, adipose tissue inflammation, impaired glucose metabolism, and obesity-related CV risk [5,18]. Although evidence remains preliminary, several studies have reported improvements in metabolic parameters following RDN, raising the possibility that autonomic modulation may influence cardiometabolic health through mechanisms extending beyond hemodynamic regulation [18].

Collectively, these observations support a broader biological framework in which RDN influences interconnected neurohumoral, inflammatory, vascular, cardiac, renal, and metabolic pathways. The principal mechanisms through which RDN may exert disease-modifying effects beyond BP reduction are summarized in Fig. 2.

Fig. 2. Mechanisms of disease modification beyond blood pressure reduction. Potential biological pathways through which RDN exerts effects beyond blood pressure lowering. Sympathetic modulation influences neurohumoral signaling, immune activation, oxidative stress, endothelial function, cardiac remodeling, and renal injury. These interconnected mechanisms may explain the broader cardiovascular and renal benefits observed following RDN.

RDN, renal denervation; RAAS, renin–angiotensin–aldosterone system; LV, left ventricular; AF, atrial fibrillation.

Rather than functioning solely as an antihypertensive procedure, RDN may modify fundamental mechanisms that contribute to disease initiation and progression across multiple organ systems. This mechanistic perspective provides the foundation for evaluating RDN within a disease-modification paradigm and helps explain its emerging therapeutic potential beyond resistant hypertension. A summary of the major pathophysiological pathways potentially affected by RDN is presented in Table 1.

Table 1. Pathophysiological mechanisms supporting renal denervation as an autonomic disease-modifying therapy.

Mechanism	Effect of sympathetic overactivity	Potential effect of renal denervation	Clinical implications
Neurohumoral activation	Increased RAAS activity	Reduced neurohumoral signaling	BP reduction, organ protection
Inflammation	Increased cytokine production	Attenuation of inflammatory pathways	Reduced vascular injury
Oxidative stress	Increased ROS generation	Improved redox balance	Improved endothelial function
Endothelial dysfunction	Reduced nitric oxide bioavailability	Enhanced endothelial homeostasis	Improved vascular health
Cardiac remodeling	LVH, fibrosis, diastolic dysfunction	Reverse remodeling	HF and AF prevention
Renal injury	Glomerular hypertension, fibrosis	Renoprotective effects	Slower CKD progression
Metabolic dysfunction	Insulin resistance	Improved metabolic regulation	Reduced cardiometabolic risk

RAAS, renin–angiotensin–aldosterone system; BP, blood pressure; ROS, reactive oxygen species; LVH, left ventricular hypertrophy; HF, heart failure; AF, atrial fibrillation; CKD, chronic kidney disease.

CLINICAL EVIDENCE FOR AUTONOMIC DISEASE MODIFICATION

Growing evidence indicates that the therapeutic effects of RDN extend beyond BP reduction and are accompanied by measurable improvements in autonomic nervous system function. While BP represents the principal clinical endpoint in most randomized trials, physiological markers of sympathetic activity provide more direct evidence of the biological effects of RDN. Improvements in heart rate variability (HRV), resting heart rate, nocturnal BP dipping, muscle sympathetic nerve activity (MSNA), and renal norepinephrine spillover collectively support the concept that RDN attenuates pathological sympathetic activation and restores autonomic homeostasis [7,19,20,21]. These physiological changes constitute the mechanistic foundation for the emerging paradigm of RDN as an autonomic disease-modifying therapy rather than merely a BP-lowering intervention.

Direct evidence of autonomic modulation

HRV

HRV is one of the most extensively validated non-invasive markers of autonomic nervous system function and reflects the dynamic interplay between sympathetic and parasympathetic activity. Reduced HRV is a well-established manifestation of autonomic dysfunction and has consistently been associated with resistant hypertension, HF, AF, CKD, diabetes mellitus, and increased CV mortality [15,19,20,21]. Because RDN directly targets renal sympathetic afferent and efferent pathways, improvement in HRV provides an important physiological indicator that the procedure exerts biological effects beyond BP reduction.

Several clinical investigations have demonstrated favorable changes in HRV following RDN. Improvements have been observed in both time-domain indices, including the standard deviation of normal-to-normal RR intervals (SDNN) and the root mean square of successive RR interval differences (RMSSD), as well as frequency-domain parameters reflecting reduced sympathetic predominance and enhanced parasympathetic activity [22,23,24,25]. Although the magnitude of these changes varies according to study population, duration of follow-up, and analytical methodology, the overall direction of evidence consistently supports autonomic rebalancing after successful RDN.

Importantly, HRV may provide information that is complementary rather than redundant to BP measurements. Several studies have reported improvement in HRV despite only modest reductions in office BP, suggesting that restoration of autonomic homeostasis may occur independently of the magnitude of antihypertensive response [23,26]. This observation challenges the traditional definition of procedural success based exclusively on BP reduction and supports the concept that physiological evidence of sympathetic modulation should also be considered when evaluating treatment efficacy.

Beyond its role as an outcome measure, HRV may also contribute to patient selection. Individuals with markedly impaired baseline HRV are more likely to exhibit pronounced sympathetic activation and may therefore derive greater benefit from sympathetic modulation through RDN [7,20,22]. Although prospective validation remains limited, HRV represents one of the most promising candidate biomarkers for identifying an autonomic responder phenotype, providing a readily available, reproducible, and non-invasive tool that could facilitate precision-based selection of patients most likely to benefit from RDN.

Resting and ambulatory heart rate

Resting heart rate is a readily available clinical marker of autonomic balance and, in hypertensive populations, may provide indirect information regarding the degree of sympathetic activation. Elevated heart rate is associated with increased adrenergic drive and adverse CV risk; however, it is influenced by several non-autonomic factors, including physical fitness, emotional stress, thyroid function, medications, anemia, and concomitant CV disease. Heart rate should therefore not be interpreted as a direct or isolated measure of sympathetic activity. Nevertheless, changes in resting or ambulatory heart rate after RDN may provide complementary evidence of autonomic modulation when considered alongside BP, HRV, and more direct physiological measurements.

In the randomized, sham-controlled SPYRAL HTN-OFF MED trial, RDN produced a significant reduction in 24-hour ambulatory heart rate at 3 months compared with the sham procedure. The reduction was particularly evident during the morning period, when sympathetic activity is typically increased. Importantly, participants with a baseline 24-hour heart rate above the study median experienced substantially greater reductions in ambulatory BP than those with lower baseline heart rates, suggesting that elevated pretreatment heart rate may identify a subgroup with a more prominent sympathetic component to hypertension and a greater likelihood of responding to RDN [27].

Consistent findings have been reported in patients with resistant hypertension. Ukena et al. [28] observed reductions in 24-hour heart rate after RDN, particularly among patients with elevated baseline heart rate. The same study also evaluated HRV and premature atrial contractions, thereby supporting the possibility that RDN influences both tonic cardiac sympathetic activity and beat-to-beat autonomic regulation. However, the magnitude and consistency of these effects varied across patients, indicating that heart rate reduction is not a universal consequence of renal nerve ablation.

The effect of RDN on heart rate has also been examined during physiological stress. In a study using standardized exercise testing, RDN was associated with reductions in heart rate at rest, at peak exercise, and during post-exercise recovery. These findings suggest that the autonomic effects of RDN may extend beyond resting conditions and influence chronotropic responses during sympathetic activation. Nevertheless, the study was relatively small and was not sham-controlled, limiting the certainty with which these changes can be attributed specifically to renal nerve interruption [29].

Beyond its role as a treatment outcome, baseline heart rate has emerged as a potential predictor of antihypertensive response. A systematic review and meta-analysis of patient-specific response predictors found that higher baseline heart rate was associated with a greater reduction in 24-hour systolic BP following RDN. This association supports the hypothesis that patients with a stronger sympathetic contribution to their hypertension may obtain greater hemodynamic benefit from renal neuromodulation [30]. However, available studies do not establish a universally validated heart-rate threshold, and the predictive value of resting heart rate may be modified by medication use, rhythm status, age, fitness, and comorbidities.

Overall, reductions in resting and ambulatory heart rate provide clinically accessible evidence consistent with autonomic modulation after RDN, particularly in patients with elevated baseline heart rate. At the same time, neutral heart-rate findings have been reported in some long-term cohorts, and heart rate remains an imperfect surrogate of sympathetic activity. Accordingly, heart rate should not be used alone to define procedural success or candidacy for RDN. Its greatest potential may lie in a multiparametric autonomic phenotype combining baseline heart rate with HRV, ambulatory BP patterns, direct indices of sympathetic activity, target-organ involvement, and clinical characteristics.

Nocturnal BP dipping

Under physiological conditions, BP declines during sleep by approximately 10–20% relative to daytime values. Attenuation or reversal of this nocturnal decline, manifesting as a non-dipping or reverse-dipping pattern, is common in resistant hypertension and is associated with autonomic dysregulation, OSA, CKD, diabetes mellitus, increased target-organ damage, and adverse CV outcomes [31,32]. Because excessive sympathetic activity contributes to both nocturnal hypertension and disruption of normal circadian BP regulation, nighttime BP and dipping status may provide clinically relevant, although indirect, markers of the autonomic effects of RDN.

Contemporary sham-controlled RDN trials have demonstrated a broadly distributed BP-lowering effect across the 24-hour cycle rather than an effect confined to office or daytime measurements. Analyses of the SPYRAL HTN program showed reductions in nighttime, early-morning, daytime, and 24-hour ambulatory BP, supporting the concept of an “always-on” therapeutic effect that is independent of medication dosing time [32,33]. This characteristic may be particularly relevant in patients with nocturnal hypertension, in whom the effects of once-daily antihypertensive medications may diminish overnight.

The most detailed long-term evaluation was provided by a pooled post-hoc analysis of 388 patients who underwent radiofrequency RDN in the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED trials. At baseline, 96.1% of participants had nocturnal hypertension, while 51.3% were classified as non-dippers and 9.8% as reverse dippers or risers. At 2 years, nighttime systolic BP had decreased by 12.0 ± 17.1 mmHg in the overall cohort, and the prevalence of nocturnal hypertension had declined by 27.4%. The greatest nighttime systolic BP reduction occurred among patients with a baseline riser pattern, in whom nighttime systolic BP decreased by 23.7 ± 14.3 mmHg [34].

These observations suggest that patients with the most disturbed circadian BP profiles may derive substantial nighttime BP benefit from RDN. However, a reduction in nighttime BP should not automatically be interpreted as restoration of physiological dipping. Dipping status is determined by the ratio between nighttime and daytime BP; therefore, parallel reductions during both periods may lower absolute nighttime BP without changing the dipping category. Moreover, the available long-term SPYRAL analysis included only RDN-treated participants, combined data from trials with different medication protocols, and permitted changes in antihypertensive treatment after the primary endpoint [34]. Consequently, the evidence more firmly supports sustained reduction of nocturnal BP than definitive normalization of the dipping pattern.

Earlier observational studies similarly reported reductions in nighttime ambulatory BP after RDN, although the magnitude of nocturnal reduction was generally smaller than that observed for office BP and varied substantially among individuals [35]. Experimental data provide additional biological plausibility by demonstrating that renal nerve interruption can improve circadian BP variation through modulation of sympathetic activity, renin–angiotensin system rhythmicity, and molecular clock pathways; however, these mechanistic findings have not yet been fully validated in humans [36].

Accordingly, nighttime BP and dipping phenotype should be considered complementary components of autonomic assessment rather than stand-alone measures of procedural success. Ambulatory BP monitoring (ABPM) before and after RDN may identify patients with nocturnal hypertension or reverse dipping who could derive particular benefit, while also providing a reproducible measure of the procedure’s continuous 24-hour effect. Future sham-controlled studies should prospectively evaluate conversion between dipping phenotypes, control for medication timing and adherence, and determine whether improvement in nocturnal BP translates into reductions in CV and renal events.

MSNA and renal norepinephrine spillover

MSNA and renal norepinephrine spillover provide the most direct physiological and neurochemical assessments of sympathetic activity used in human RDN research. MSNA is measured by microneurography of postganglionic sympathetic fibers supplying skeletal-muscle vasculature, whereas renal norepinephrine spillover quantifies the net release of norepinephrine from renal sympathetic nerves using radiotracer dilution and renal venous sampling. In contrast to heart rate, HRV, or ambulatory BP patterns, these techniques assess sympathetic neural traffic more directly and therefore provide important mechanistic evidence that RDN acts through renal and central sympathoinhibition.

The initial proof-of-concept study of catheter-based RDN evaluated renal norepinephrine spillover in a subgroup of patients with resistant hypertension. Bilateral renal nerve ablation produced a mean reduction of approximately 47% in renal norepinephrine spillover at 1 month, providing direct evidence that the procedure substantially attenuated renal efferent sympathetic activity [37]. In an intensively characterized patient, this reduction was accompanied by decreased whole-body norepinephrine spillover, reduced MSNA, lower plasma renin activity, and increased renal plasma flow, suggesting that interruption of both efferent and afferent renal pathways may influence systemic sympathetic outflow as well as intrarenal neurohumoral regulation [37,38].

Subsequent microneurographic studies provided further evidence of central sympathoinhibition. Hering et al. [39] demonstrated marked reductions in multiunit MSNA and single-unit sympathetic firing after RDN in patients with resistant hypertension. The procedure reduced the firing probability of individual vasoconstrictor neurons and the incidence of multiple firing within a single cardiac cycle, indicating modification not only of the frequency but also of the pattern and intensity of central sympathetic discharge.

Longitudinal analyses have generally supported a reduction in MSNA after RDN, although the relationship with BP response has not been uniform. In a time-integrated analysis of repeated measurements in patients with resistant hypertension, Seravalle et al. [40] observed significant reductions in both MSNA and BP after bilateral RDN. The trajectories of sympathetic activity and BP declined in parallel over time at the group level, supporting a mechanistic role for sympathoinhibition in the antihypertensive effect of the procedure. Nevertheless, individual changes in MSNA and BP were not consistently correlated, indicating that sympathetic inhibition does not translate into an identical hemodynamic response in every patient.

More recent data have reinforced this overall signal while illustrating the complexity of regional autonomic responses. In patients with resistant or uncontrolled hypertension, Dell’Oro et al. [41] found that RDN reduced muscle sympathetic nerve traffic over short-term follow-up, whereas skin sympathetic nerve activity showed a different response. These findings suggest that RDN does not produce uniform suppression of all sympathetic outflows but may preferentially influence neural pathways involved in CV and vasomotor regulation.

Despite their mechanistic value, MSNA and renal norepinephrine spillover have important limitations. Microneurography is technically demanding, operator dependent, and generally restricted to specialized autonomic laboratories. Renal norepinephrine spillover requires invasive renal venous catheterization, radiotracer infusion, and specialized analytical expertise, making it unsuitable for routine clinical use. In addition, studies have generally enrolled small, highly selected cohorts, and reductions in MSNA have not been demonstrated consistently across all investigations. Variability may reflect incomplete denervation, differences in ablation technique, medication changes, baseline sympathetic activity, or the inability of peripheral MSNA to fully represent organ-specific sympathetic responses.

Therefore, MSNA and renal norepinephrine spillover currently serve primarily as research tools rather than practical clinical biomarkers. Their findings nevertheless provide some of the strongest direct evidence that RDN can reduce renal sympathetic neurotransmission and modify central sympathetic outflow. Future trials should incorporate standardized autonomic substudy protocols, contemporary ablation technologies, sham controls, and repeated measurements to determine whether the magnitude of sympathoinhibition predicts sustained BP reduction, target-organ protection, or benefit beyond conventional hemodynamic endpoints.

Clinical implications across disease states

The mechanistic rationale for considering RDN as an autonomic disease-modifying therapy has increasingly been supported by clinical observations across CV, renal, and metabolic disease states. Although hypertension remains the most established indication for RDN, several studies have explored its effects in conditions characterized by heightened sympathetic activity, including AF, HF, CKD, OSA, and metabolic dysfunction [11,12,26,42]. These investigations remain heterogeneous in design and sample size; however, collectively they suggest that the therapeutic implications of renal sympathetic modulation may extend beyond conventional BP reduction.

AF

AF is strongly influenced by autonomic imbalance, with both sympathetic activation and parasympathetic fluctuations contributing to atrial electrical instability, triggered activity, and substrate progression. Hypertension further promotes AF through left atrial remodeling, fibrosis, increased filling pressures, and neurohumoral activation. Given the central role of sympathetic overactivity in both hypertension and AF, RDN has been investigated as an adjunctive strategy to catheter ablation.

The ERADICATE-AF randomized clinical trial provided the most important clinical evidence in this field. In patients with paroxysmal AF and hypertension undergoing pulmonary vein isolation, adjunctive RDN significantly improved freedom from recurrent AF compared with pulmonary vein isolation alone [12]. Subsequent analyses of ERADICATE-AF suggested that the antiarrhythmic benefit of RDN could not be explained solely by BP lowering, supporting the hypothesis that autonomic modulation may contribute directly to reduced AF recurrence. Additional observational and mechanistic studies have similarly suggested that RDN may reduce AF burden or delay subclinical AF development in patients with hypertensive heart disease [26].

These findings are clinically relevant because they position RDN not merely as a BP-lowering procedure but as a potential upstream therapy targeting autonomic and structural contributors to AF. Nevertheless, available evidence remains insufficient to support routine use of RDN for AF prevention outside selected research or highly specialized settings. Larger sham-controlled trials with rhythm monitoring, autonomic phenotyping, and longer follow-up are required to determine whether RDN can meaningfully alter AF progression.

Heart failure

HF is characterized by sustained sympathetic activation, neurohumoral dysregulation, renal sodium retention, and progressive cardiac remodeling. These mechanisms are particularly relevant in HF with preserved ejection fraction (HFpEF), where hypertension, obesity, renal dysfunction, arterial stiffness, and autonomic imbalance frequently coexist. Because renal sympathetic signaling contributes to both central sympathetic outflow and renal–cardiac interactions, RDN has been proposed as a potential therapeutic strategy in selected patients with HF.

The Renal Denervation in Heart Failure With Preserved Ejection Fraction trial was an early phase II study evaluating the feasibility and physiological effects of RDN in HFpEF [42]. Although limited by small sample size and open-label design, the study provided preliminary evidence that RDN may influence cardiac structure, exercise physiology, and neurohumoral activation in this population. More recent reviews and translational studies have reinforced the biological plausibility of RDN in HFpEF, particularly through attenuation of renal inflammation, fibrosis, and maladaptive sympathetic signaling [11,43].

In HF with reduced ejection fraction, the rationale for RDN is similarly based on the adverse prognostic role of sympathetic overactivity and renal neurohumoral activation. However, clinical evidence remains less mature, and the field is still limited by small studies, variable patient selection, and heterogeneous endpoints. Therefore, while HF represents one of the most conceptually attractive indications for autonomic disease modification, definitive outcome data are still lacking.

CKD

CKD is both a consequence and a driver of sympathetic overactivity. Reduced renal function is associated with increased central sympathetic outflow, RAAS activation, sodium retention, endothelial dysfunction, and progressive target-organ damage. This creates a bidirectional cardio-renal-autonomic loop in which renal injury amplifies sympathetic activity, which in turn accelerates CV and renal disease progression [4,44].

RDN has therefore attracted interest as a potential therapy for hypertensive patients with CKD. A meta-analysis evaluating RDN in CKD suggested that the procedure may reduce BP without causing significant deterioration in renal function, although the available evidence was limited by small sample sizes and heterogeneous study designs [43]. Contemporary reviews have emphasized that RDN in CKD should be viewed through a dual framework: reducing BP while potentially attenuating pathological renal–CNS signaling [18,45]. This concept is particularly relevant because patients with CKD are often difficult to treat pharmacologically, are at high CV risk, and frequently exhibit treatment-resistant hypertension.

Despite these promising signals, CKD remains an area requiring caution. Many pivotal RDN trials excluded patients with advanced renal dysfunction, and robust long-term data on renal outcomes are still limited. Future studies should clarify whether RDN can slow eGFR decline, reduce albuminuria, or improve cardio-renal outcomes independently of BP reduction.

Metabolic dysfunction and obstructive sleep apnea

Sympathetic overactivity is also implicated in metabolic syndrome, insulin resistance, obesity-related hypertension, and OSA. These conditions frequently coexist and form a pathophysiological cluster characterized by heightened adrenergic tone, intermittent hypoxia, systemic inflammation, and vascular dysfunction. Early clinical studies suggested that RDN may improve glucose metabolism and sleep apnea severity in patients with resistant hypertension and OSA [18,46].

The metabolic effects of RDN remain an evolving area of investigation. Preclinical data suggest that renal sympathetic interruption may improve insulin sensitivity and reduce hepatic insulin resistance through modulation of autonomic and inflammatory pathways [13]. More recent reviews have highlighted the potential role of RDN in glycemic regulation, while emphasizing that existing human data remain preliminary and hypothesis-generating [47]. Therefore, although metabolic dysfunction represents an appealing extension of the autonomic disease-modification paradigm, it currently requires more rigorous clinical validation.

Overall, the clinical evidence beyond hypertension remains promising but not definitive. The strongest data currently exist for BP reduction and selected AF populations, whereas evidence in HF, CKD, and metabolic disease is still emerging. Nonetheless, the consistency of mechanistic rationale across these disease states supports the broader hypothesis that RDN may target a shared autonomic substrate rather than a single hemodynamic phenotype.

The available clinical evidence supporting potential disease-modifying effects of RDN across various CV, renal, and metabolic conditions is summarized in Table 2 [13,18,42,44,48].

Table 2. Clinical evidence supporting the potential disease-modifying effects of renal denervation beyond hypertension.

Disease state	Mechanistic rationale	Key studies	Main findings
AF	Autonomic remodeling	ERADICATE-AF	Reduced AF recurrence
HFpEF	Sympathetic activation, fibrosis	Patel [42]	Improved physiological parameters
HFrEF	Neurohumoral activation	Pilot studies	Feasibility and safety demonstrated
CKD	Reno-central sympathetic signaling	Xia et al. [44], Bosch et al. [48]	BP reduction without major renal deterioration
OSA	Intermittent sympathetic activation	Witkowski et al. [18]	Improved BP and sleep apnea indices
Metabolic syndrome	Insulin resistance	Witkowski et al. [18], Koutra et al. [13]	Potential metabolic improvement

AF, atrial fibrillation; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; CKD, chronic kidney disease; OSA, obstructive sleep apnea; BF, blood pressure.

THE AUTONOMIC RESPONDER PHENOTYPE

Biological rationale

Growing evidence suggests that hypertension should no longer be regarded as a homogeneous hemodynamic disorder but rather as a biologically heterogeneous syndrome in which multiple pathophysiological mechanisms contribute to disease initiation and progression. Although elevated BP remains the defining clinical manifestation, the relative contribution of sympathetic overactivity varies substantially among individual patients. Consequently, 2 patients with similar office or ambulatory BP measurements may exhibit markedly different autonomic profiles, neurohumoral activation, target-organ involvement, and responses to therapeutic interventions [4,7,9,19,49].

The antihypertensive effect of RDN is mediated through interruption of both efferent and afferent renal sympathetic nerves. Ablation of efferent fibers reduces renin secretion, renal tubular sodium reabsorption, and renal vasoconstriction, whereas interruption of afferent renal signaling attenuates central sympathetic outflow. This bidirectional neuromodulatory mechanism provides the biological basis for systemic sympathoinhibition extending beyond renal physiology alone [4,5,6,21,37,50]. Consequently, the therapeutic effects of RDN are increasingly recognized to include modulation of neurohumoral activation, inflammatory signaling, oxidative stress, endothelial dysfunction, cardiac remodeling, renal protection, and metabolic regulation, all of which are closely linked to chronic sympathetic activation.

Despite these mechanistic observations, clinical response to RDN remains heterogeneous. Contemporary sham-controlled randomized trials have consistently demonstrated significant reductions in ambulatory BP at the population level; however, considerable interindividual variability persists, with some patients exhibiting substantial BP reductions whereas others derive only modest antihypertensive benefit [2,3,51]. This variability cannot be fully explained by procedural technique or medication adherence alone, suggesting that differences in underlying disease biology contribute importantly to treatment response.

Traditionally, patient selection for RDN has relied predominantly on BP severity, resistant hypertension status, medication burden, and anatomical suitability of the renal arteries. While these factors remain essential for determining procedural eligibility, they do not necessarily identify patients in whom sympathetic overactivity represents the dominant driver of hypertension and CV injury. BP itself represents a downstream hemodynamic phenotype resulting from multiple interacting mechanisms, including arterial stiffness, sodium retention, vascular remodeling, neurohumoral activation, obesity, aging, and genetic susceptibility. Therefore, reliance on BP alone may incompletely characterize the biological substrate most likely to respond to sympathetic modulation [5,8,52].

These observations support a transition from conventional BP-based patient selection toward physiology-guided precision phenotyping. Rather than assuming that all patients with resistant hypertension share the same pathophysiological mechanism, precision medicine seeks to identify the predominant biological pathway responsible for disease in each individual patient. Within this framework, patients demonstrating objective evidence of sympathetic overactivity may constitute a distinct subgroup with greater potential to benefit from RDN. This concept forms the basis of the proposed autonomic responder phenotype, in which treatment selection is guided not only by BP level but also by physiological evidence of autonomic dysregulation and sympathetic target-organ injury [8,52].

Importantly, the autonomic responder phenotype should not be interpreted as a single diagnostic entity or as being defined by one biomarker alone. Current evidence does not support the use of any isolated physiological measurement as a definitive predictor of response to RDN. Instead, sympathetic activation should be viewed as a multidimensional construct incorporating complementary information obtained from ABPM, HRV, resting heart rate, direct measures of sympathetic activity, neurohumoral biomarkers, evidence of target-organ damage, and renal artery anatomy. Integration of these domains is likely to provide greater biological specificity than any individual parameter considered in isolation [1,8,52].

Accordingly, the autonomic responder phenotype represents a conceptual precision medicine framework rather than a validated clinical scoring system. Its objective is to identify patients in whom excessive sympathetic activation is a principal contributor to disease pathogenesis and therefore a rational therapeutic target for RDN. Prospective validation of this framework using standardized autonomic biomarkers and phenotype-enriched randomized trials will be required before routine implementation in clinical practice.

Candidate biomarkers for patient selection

Identifying patients most likely to benefit from RDN remains one of the principal challenges in contemporary hypertension management. Although resistant hypertension has historically been the primary indication for RDN, accumulating evidence indicates that BP severity alone incompletely reflects the underlying biological mechanisms driving disease. Consequently, increasing attention has shifted toward the identification of physiological and structural biomarkers that better characterize sympathetic activation and may facilitate precision-based patient selection [1,52].

Among currently available clinical tools, ABPM provides the most informative assessment of the hemodynamic phenotype. In addition to confirming persistent hypertension, ABPM identifies nocturnal hypertension, non-dipping or reverse-dipping patterns, exaggerated morning BP surge, and increased short-term BP variability, all of which have been associated with enhanced SNS activity [31,53,54,55]. Because RDN exerts continuous neuromodulatory effects throughout the 24-hour period, abnormalities detected by ABPM may better reflect sympathetic dysregulation than isolated office BP measurements. Nevertheless, none of these parameters has been prospectively validated as an independent predictor of procedural success.

Non-invasive autonomic biomarkers may further refine patient phenotyping. Persistently elevated resting heart rate has consistently been associated with increased sympathetic tone and, in several post hoc analyses, has been linked to greater ambulatory BP reduction following RDN [27,30]. Likewise, impaired HRV, reflected by reduced SDNN, RMSSD, or altered frequency-domain indices, identifies autonomic imbalance and has emerged as a promising marker of sympathetic predominance [19,20,28]. Although HRV is influenced by age, cardiac rhythm, medication use, physical conditioning, and several comorbidities, integration of HRV with ambulatory BP characteristics may improve identification of patients with a predominantly neurogenic hypertensive phenotype.

Direct physiological measurements of sympathetic activity provide the strongest mechanistic evidence but remain largely confined to research settings. MSNA measured by microneurography and renal norepinephrine spillover assessed using isotope dilution techniques directly quantify sympathetic neural activity and have demonstrated significant reductions following RDN [38,40,56,57,58]. However, their invasive nature, technical complexity, limited availability, and lack of standardized thresholds preclude routine clinical implementation. At present, these methods should be regarded primarily as reference standards for mechanistic investigations rather than practical biomarkers for everyday patient selection.

Assessment of sympathetic target-organ injury provides an additional dimension of biological phenotyping. LVH, impaired diastolic function, CKD, albuminuria, AF, HF, OSA, and metabolic dysfunction all represent clinical manifestations strongly associated with chronic sympathetic activation [10,11,13,16,59]. Although none of these conditions independently establishes an indication for RDN, their coexistence may indicate a greater burden of sympathetic-mediated disease and therefore strengthen the biological rationale for autonomic modulation. Future studies should determine whether combinations of target-organ characteristics improve prediction of therapeutic response compared with BP measurements alone.

Beyond physiological phenotype, procedural feasibility remains an essential prerequisite for successful RDN. Anatomical factors including renal artery diameter, vessel length, early branching, accessory renal arteries, arterial calcification, fibromuscular dysplasia, prior renal artery intervention, and the ability to achieve circumferential ablation significantly influence procedural efficacy [1,3,52]. Furthermore, procedural variables—including catheter technology, ultrasound versus radiofrequency energy delivery, number and distribution of ablation points, and completeness of circumferential nerve interruption—may contribute substantially to treatment variability and should be considered alongside patient-related factors.

Taken together, currently available evidence does not support reliance on any single biomarker for patient selection. Instead, the autonomic responder phenotype should be regarded as a multidimensional construct integrating clinical presentation, ambulatory BP characteristics, autonomic biomarkers, evidence of sympathetic target-organ injury, and anatomical suitability for RDN. The principal clinical, physiological, anatomical, and procedural characteristics that may contribute to identification of the autonomic responder phenotype are summarized in Table 3. Such an approach aligns with the principles of precision medicine by recognizing that sympathetic overactivity exists along a biological continuum rather than as a binary characteristic. Prospective validation of composite prediction models incorporating these domains represents an important priority for future RDN research.

Table 3. Candidate biomarkers and precision-based selection criteria for identification of the autonomic responder phenotype before renal denervation.

Phenotyping domain	Candidate biomarker/characteristic	Physiological rationale	Potential role in patient selection
Clinical phenotype	Resistant or uncontrolled hypertension	Persistent hypertension despite optimized therapy increases the likelihood of sympathetic contribution	Essential first-step screening
Clinical phenotype	Young age/early-onset hypertension	Greater neurogenic contribution before advanced vascular remodeling	Supportive
ABPM	Nocturnal hypertension	Reflects sustained sympathetic activation during sleep	Essential
ABPM	Reverse- or non-dipping pattern	Circadian autonomic dysregulation	Essential
ABPM	Morning BP surge	Marker of increased adrenergic activation	Supportive
ABPM	Increased 24-hr BP variability	Suggests autonomic instability	Adjunctive
Autonomic biomarkers	Elevated resting heart rate	Indirect marker of sympathetic overactivity	Supportive
Autonomic biomarkers	Reduced HRV (SDNN, RMSSD, low frequency/high frequency)	Sympathetic predominance with reduced vagal modulation	Supportive
Research biomarkers	MSNA	Direct assessment of sympathetic neural traffic	Research only
Research biomarkers	Renal norepinephrine spillover	Direct quantification of renal sympathetic activity	Research only
Cardiac phenotype	Left ventricular hypertrophy	Marker of chronic sympathetic-mediated target-organ injury	Supportive
Cardiac phenotype	Diastolic dysfunction	Reflects chronic neurohumoral activation and myocardial remodeling	Adjunctive
Renal phenotype	Albuminuria	Marker of sympathetic-mediated renal injury	Supportive
Renal phenotype	Chronic kidney disease	Indicates cardiorenal sympathetic activation	Supportive
Comorbidities	Atrial fibrillation	Autonomic remodeling and atrial sympathetic activation	Adjunctive
Comorbidities	Heart failure	Excessive sympathetic activation and neurohumoral dysregulation	Adjunctive
Comorbidities	Obstructive sleep apnea	Chronic intermittent sympathetic stimulation	Supportive
Metabolic phenotype	Obesity/metabolic syndrome	Associated with chronic sympathetic activation	Adjunctive
Procedural anatomy	Suitable renal artery anatomy (diameter, length, absence of severe stenosis)	Required to achieve complete and effective denervation	Mandatory procedural criterion
Procedural factors	Ability to perform complete circumferential ablation	Determines procedural efficacy	Mandatory procedural criterion

The autonomic responder phenotype should be considered a multidimensional biological construct integrating physiological, structural, and procedural characteristics rather than a single diagnostic biomarker. Current evidence does not support using any individual parameter in isolation to determine eligibility for renal denervation.

ABPM, ambulatory blood pressure monitoring; BP, blood pressure; SDNN, standard deviation of normal-to-normal RR intervals; RMSSD, root mean square of successive RR interval differences; HRV, heart rate variability; MSNA, muscle sympathetic nerve activity.

Proposed precision-based selection algorithm

Although individual biomarkers provide valuable physiological information, current evidence does not support the use of any single parameter as a definitive predictor of response to RDN. Hypertension is a multifactorial disorder, and sympathetic activation represents only one component of its complex pathophysiology. Consequently, successful patient selection should not rely on isolated measurements but rather on integration of complementary clinical, physiological, anatomical, and procedural characteristics into a multidimensional precision medicine framework [1,8,60,61].

Based on currently available evidence, we propose a stepwise precision-based algorithm for identifying the autonomic responder phenotype (Fig. 3). The first step involves confirmation of an appropriate clinical indication according to contemporary guideline recommendations, including persistent uncontrolled or resistant hypertension despite guideline-directed medical therapy, exclusion of secondary causes of hypertension, and optimization of medication adherence and lifestyle modification [2,52,61].

Fig. 3. A precision-based clinical framework for identification of the autonomic responder phenotype before RDN. The proposed framework integrates sequential clinical, physiological, anatomical, and procedural assessments to facilitate individualized patient selection for RDN. Following confirmation of uncontrolled or resistant hypertension and exclusion of secondary causes, patients undergo ambulatory blood pressure monitoring to identify nocturnal hypertension, non-dipping or reverse-dipping patterns, morning blood pressure surge, and increased blood pressure variability. Subsequent evaluation incorporates autonomic biomarkers, including resting heart rate and heart rate variability, while direct measures of sympathetic activity, such as muscle sympathetic nerve activity and renal norepinephrine spillover, remain research tools. Evidence of sympathetic target-organ injury, including left ventricular hypertrophy, chronic kidney disease, atrial fibrillation, heart failure, obstructive sleep apnea, and metabolic dysfunction, is then integrated with renal artery anatomy and procedural feasibility. Patients demonstrating a multidimensional autonomic phenotype and appropriate anatomical characteristics are considered potential candidates for RDN within a precision medicine framework.

RDN, renal denervation.

Following confirmation of procedural eligibility, patients should undergo physiological phenotyping using ABPM. Particular attention should be given to nocturnal hypertension, reverse- or non-dipping patterns, exaggerated morning BP surge, and increased BP variability, as these characteristics may indicate enhanced sympathetic activity and provide biological rationale for autonomic modulation [31,53,54,55].

The next stage consists of assessment of autonomic function. Readily available clinical markers such as elevated resting heart rate and impaired HRV may provide indirect evidence of sympathetic predominance. In selected research settings, direct physiological assessment using MSNA or renal norepinephrine spillover may further characterize autonomic activation, although these techniques currently remain unsuitable for routine clinical practice because of their technical complexity and limited availability [27,28,30,31,38,40,41,53,54,55,57,58].

Evaluation of sympathetic target-organ involvement represents the subsequent component of patient phenotyping. The presence of LVH, CKD, albuminuria, AF, HF, OSA, metabolic dysfunction, or other manifestations of chronic sympathetic activation may strengthen the biological rationale for RDN by indicating that sympathetic overactivity contributes not only to BP elevation but also to progressive CV and renal injury [10,11,13,16,59].

Finally, detailed assessment of renal artery anatomy and procedural feasibility remains indispensable before intervention. Appropriate vessel diameter and length, absence of significant renal artery stenosis or fibromuscular dysplasia, recognition of accessory renal arteries, and selection of the optimal ablation technology all influence procedural success and should be integrated into the final treatment decision [8,52,60,61].

Importantly, this proposed algorithm should not be interpreted as a validated clinical prediction model. Rather, it represents a conceptual framework synthesizing current mechanistic, physiological, and clinical evidence to facilitate individualized patient selection. Future prospective studies should evaluate composite prediction models incorporating autonomic biomarkers, ambulatory BP characteristics, imaging findings, procedural variables, and machine-learning approaches to determine whether precision phenotyping improves procedural efficacy and long-term CV outcomes compared with conventional BP-based selection alone.

The concept of the autonomic responder phenotype therefore shifts the therapeutic paradigm from identifying patients with the highest BP toward identifying patients in whom sympathetic overactivity is the predominant driver of disease biology. A proposed precision-based framework integrating clinical, physiological, anatomical, and procedural characteristics for identification of the autonomic responder phenotype is illustrated in Fig. 3.

Such a transition represents a critical step toward precision CV medicine and may ultimately expand the role of RDN beyond conventional antihypertensive therapy.

FUTURE RESEARCH PRIORITIES AND EMERGING FRONTIERS

Procedural innovation and verification of successful denervation

Despite the substantial progress achieved in contemporary sham-controlled clinical trials, several procedural limitations continue to constrain the reproducibility and predictability of RDN. Current catheter-based technologies effectively reduce BP at the population level; however, considerable interindividual variability in treatment response persists despite standardized procedural protocols. This variability reflects not only differences in patient biology but also important procedural factors, including renal nerve anatomy, completeness of circumferential ablation, energy delivery, and the absence of reliable intraprocedural confirmation of successful denervation [1,2,52,62,63].

One of the greatest unmet procedural challenges is the inability to determine, during the intervention, whether sufficient sympathetic nerve disruption has been achieved. Unlike electrophysiological ablation procedures, where electrical conduction block can be directly confirmed, RDN currently lacks an objective procedural endpoint that verifies effective interruption of renal sympathetic signaling. Consequently, operators must rely primarily on anatomical assumptions, device-specific ablation protocols, and procedural experience rather than direct physiological evidence of treatment success [64,65].

Technological innovation is therefore expected to represent one of the major drivers of future progress. First-generation single-electrode radiofrequency systems have largely been replaced by multi-electrode radiofrequency catheters and ultrasound-based platforms capable of achieving more circumferential and reproducible nerve ablation. These newer systems have demonstrated improved procedural consistency and have formed the basis of the contemporary sham-controlled trials that re-established the efficacy of RDN [1,3,63]. Nevertheless, further refinement remains necessary because renal sympathetic nerve distribution exhibits substantial interindividual variability with respect to nerve depth, circumferential location, and distal branching, factors that cannot currently be visualized during intervention [66,67].

Future procedural advances are therefore likely to focus on objective verification of successful denervation rather than solely improving energy delivery. Several investigational strategies have been proposed, including renal nerve stimulation before and after ablation, high-resolution intravascular imaging, electrophysiological mapping of sympathetic fibers, measurement of local neurochemical biomarkers, and assessment of acute physiological responses immediately following treatment. Although none of these techniques has yet been validated for routine clinical practice, they represent promising approaches for transforming RDN from an anatomically guided procedure into a biologically guided intervention [64,66,67,68].

Another important area of development is procedural standardization. Contemporary clinical trials employ different ablation technologies, catheter designs, energy modalities, and treatment protocols, making direct comparison across studies challenging. Future investigations should establish standardized definitions of procedural completeness, minimum ablation requirements, optimal treatment of accessory renal arteries, and quality-control metrics to improve reproducibility across centers. Such standardization may also facilitate comparison between radiofrequency, ultrasound, chemical, and emerging energy-based denervation technologies [52,62,63].

Beyond hardware innovation, integration of computational technologies may further improve procedural precision. Artificial intelligence (AI)-assisted image analysis, 3-dimensional reconstruction of renal artery anatomy, patient-specific procedural planning, and computational prediction of optimal ablation sites may enable individualized treatment strategies based on anatomical and physiological characteristics rather than standardized ablation patterns. Although these approaches remain investigational, they align closely with the broader transition toward precision CV intervention [69,70].

Ultimately, future procedural success should not be defined solely by technical completion of ablation but by objective demonstration of effective autonomic modulation. Development of reliable intraprocedural biomarkers confirming sympathetic nerve disruption would represent a major advance for the field, reducing treatment variability, improving procedural reproducibility, and strengthening the relationship between successful denervation and long-term clinical outcomes. Such innovations may prove essential for establishing RDN as a mature precision-based autonomic therapy rather than simply a device-based antihypertensive procedure. The evolution of RDN technologies and future procedural innovations aimed at improving treatment precision and verification of successful denervation are summarized in Fig. 4.

Fig. 4. Technological evolution of RDN from anatomical ablation toward precision-guided autonomic intervention. The figure illustrates the anticipated evolution of RDN technologies across 4 developmental stages. Early-generation catheter systems relied primarily on anatomical renal artery ablation without objective confirmation of sympathetic nerve interruption. Contemporary technologies employ multi-electrode RF and ultrasound-based platforms with improved circumferential energy delivery and greater procedural consistency. Future technological development is expected to focus on objective verification of successful denervation through physiological assessment, intraprocedural biomarkers, renal nerve mapping, and advanced imaging techniques. Ultimately, integration of computational planning, AI, patient-specific anatomical modeling, and biological feedback systems may enable precision-guided autonomic intervention with individualized procedural optimization.

RDN, renal denervation; RF, radiofrequency; AI, artificial intelligence.

Expansion beyond hypertension: a trial agenda

Although hypertension remains the only established clinical indication for RDN, accumulating mechanistic and early clinical evidence suggests that its therapeutic potential may extend to a broader spectrum of CV, renal, and metabolic disorders characterized by sympathetic overactivity. Importantly, the biological rationale for these indications derives not from BP reduction alone but from the central role of the autonomic nervous system in disease initiation and progression. Consequently, future clinical development of RDN should shift from disease-based indications toward phenotype-based investigation, targeting patient populations in whom sympathetic dysregulation represents a dominant pathophysiological mechanism [8,10,11,12,13,42,62,71,72,73,74,75].

Among potential future indications, HF, particularly HFpEF, represents one of the most compelling therapeutic targets. HFpEF is characterized by chronic sympathetic activation, impaired baroreflex sensitivity, systemic inflammation, endothelial dysfunction, renal impairment, and ventricular–vascular uncoupling, mechanisms that closely overlap with those targeted by RDN. Nevertheless, current evidence remains limited to mechanistic studies, small randomized trials, and surrogate physiological endpoints. Future investigations should therefore prioritize phenotype-enriched HFpEF populations with concomitant hypertension or objective evidence of sympathetic overactivity while evaluating clinically meaningful outcomes, including HF hospitalization, quality of life, exercise capacity, and CV mortality rather than BP reduction alone [10,11,42].

AF represents another promising area of investigation. Experimental and clinical evidence suggests that autonomic remodeling contributes to atrial electrical instability, structural remodeling, and maintenance of AF. Early studies combining pulmonary vein isolation with RDN have demonstrated encouraging reductions in AF recurrence among selected hypertensive patients. However, these findings remain insufficient to establish RDN as a routine adjunctive rhythm-control strategy. Future sham-controlled trials should determine whether autonomic phenotyping identifies patients who derive incremental benefit from RDN beyond contemporary catheter ablation techniques and optimal medical therapy [12,71,72].

The potential role of RDN in CKD also warrants further investigation. CKD is associated with persistent sympathetic activation, activation of the RAAS, endothelial dysfunction, and progressive cardiorenal remodeling. Although available studies suggest that RDN may safely reduce BP in selected CKD populations, its effects on preservation of kidney function, albuminuria, progression to kidney failure, and CV events remain uncertain. Dedicated randomized studies enriched for patients with demonstrable sympathetic activation and carefully monitored renal outcomes are therefore needed before routine implementation can be considered [48,73,74].

Additional disease states characterized by autonomic dysregulation—including OSA, obesity, metabolic syndrome, and type 2 diabetes mellitus—represent biologically attractive but still investigational indications. Chronic intermittent hypoxia, insulin resistance, adipose tissue inflammation, and neurohumoral activation collectively contribute to sustained sympathetic stimulation in these conditions. Whether modulation of renal sympathetic signaling can meaningfully influence these complex metabolic disorders independently of BP reduction remains unknown and should be evaluated within rigorously designed mechanistic and outcome-driven clinical trials [13,75,76].

Importantly, future expansion of RDN indications should proceed cautiously and remain grounded in robust clinical evidence. The presence of sympathetic overactivity alone should not be regarded as sufficient justification for intervention. Instead, future trials should incorporate objective autonomic phenotyping, standardized procedural techniques, sham controls, optimized background medical therapy, and clinically meaningful outcome measures to determine whether disease modification extends beyond hemodynamic improvement. Such an approach would facilitate transition from empirical disease-based indications toward biologically informed precision intervention.

Collectively, these considerations suggest that the future of RDN is unlikely to be defined by expansion into every disease associated with sympathetic activation, but rather by identification of carefully selected patient phenotypes in whom autonomic modulation addresses a central mechanism of disease. Consequently, the next generation of investigations should prioritize phenotype-enriched, mechanism-driven clinical trials rather than broad disease-based expansion alone. A proposed roadmap illustrating the future clinical development of RDN, including phenotype-guided trial design, expansion of investigational indications, and transition toward autonomic disease modification, is presented in Fig. 5.

Fig. 5. Roadmap for the future clinical development of RDN beyond conventional BP reduction. The proposed roadmap illustrates the anticipated evolution of RDN from a BP-lowering intervention toward a precision-based autonomic therapy. Future progress depends on sequential integration of phenotype-guided patient selection, procedural optimization, validation of autonomic biomarkers, standardized denervation techniques, and disease-specific clinical trials. Expansion into cardiovascular, renal, metabolic, and sleep-related disorders should be guided by objective evidence of sympathetic overactivity and supported by sham-controlled outcome trials incorporating clinically meaningful endpoints beyond BP reduction. Ultimately, validated responder phenotypes and mechanistically informed trial designs may facilitate transition from empirical antihypertensive treatment toward precision autonomic disease modification.

RDN, renal denervation; BP, blood pressure; HRV, heart rate variability; HFpEF, heart failure with preserved ejection fraction.

Future trial design: from BP reduction to clinical outcome modification

The next phase of RDN research should move beyond establishing antihypertensive efficacy toward determining whether modulation of renal sympathetic signaling translates into durable improvements in CV, renal, and metabolic outcomes. Although recent sham-controlled randomized trials have consistently demonstrated clinically meaningful reductions in ambulatory BP together with an acceptable safety profile, most available studies have been designed around surrogate hemodynamic endpoints rather than hard clinical outcomes. Consequently, whether RDN truly modifies the natural history of sympathetic-mediated disease independently of BP reduction remains an important unanswered question and represents one of the highest priorities for future investigation [1,3,51,52,62,64].

A central principle of future clinical research should be phenotype-guided enrollment rather than recruitment based solely on office or ambulatory BP thresholds. Patients with objective evidence of sympathetic overactivity—including abnormal ambulatory BP profiles, elevated resting heart rate, impaired HRV, nocturnal hypertension, non-dipping BP patterns, or evidence of sympathetic target-organ injury—may represent biologically enriched populations in whom autonomic modulation is most likely to produce clinically meaningful benefit. Such enrichment strategies may reduce treatment heterogeneity, increase statistical power, and improve identification of responder subgroups [8,62,65].

Selection of appropriate primary endpoints should also evolve beyond BP reduction alone. While changes in 24-hour ambulatory systolic BP remain appropriate efficacy measures for early device-development studies, larger confirmatory trials should increasingly incorporate disease-specific clinical outcomes. Depending on the target population, suitable primary endpoints may include major adverse CV events, CV mortality, HF hospitalization, progression of CKD, sustained decline in eGFR, AF recurrence following catheter ablation, or validated patient-reported quality-of-life measures. Demonstration of benefit across these clinically meaningful endpoints will be essential before RDN can be considered a disease-modifying rather than purely antihypertensive intervention [10,12,48,76].

Secondary endpoints should provide comprehensive assessment of physiological response to autonomic modulation. Recommended measures include ambulatory BP, resting heart rate, HRV, nocturnal BP, morning BP surge, BP variability, renal function, albuminuria, left ventricular mass, diastolic function, arterial stiffness, circulating neurohumoral biomarkers, inflammatory biomarkers, endothelial function, metabolic parameters, exercise capacity, and patient-reported functional status. Such multidimensional evaluation will improve understanding of treatment mechanisms while facilitating identification of responder phenotypes [1,8,27,28,30,31,33,40,53,54,55,56,58,77,78].

Future trials should also incorporate autonomic endpoints whenever feasible. Beyond conventional hemodynamic measurements, autonomic assessment may include standardized HRV analysis, baroreflex sensitivity, resting heart rate, MSNA, renal norepinephrine spillover, and emerging biomarkers of sympathetic activation. Although several of these techniques currently remain confined to specialized research settings, their inclusion in mechanistic substudies will strengthen understanding of how autonomic modulation mediates clinical benefit and may facilitate validation of future responder biomarkers.

Similarly, target-organ endpoints should receive greater emphasis. Evaluation of reverse cardiac remodeling, improvement in left ventricular diastolic function, reduction in albuminuria, preservation of renal function, vascular remodeling, and improvements in metabolic status may provide important evidence that RDN influences disease biology beyond BP reduction. Integration of imaging biomarkers with laboratory and physiological measurements will allow more comprehensive characterization of treatment effects across multiple organ systems [10,11,13,42,73,74,75].

Appropriate follow-up duration represents another major consideration. Most contemporary randomized studies have evaluated outcomes over relatively short periods, whereas autonomic remodeling and reversal of target-organ injury may require substantially longer observation. Future trials should therefore include follow-up extending to at least 24–36 months to evaluate durability of BP reduction, medication burden, CV events, renal outcomes, and long-term safety [10,51,52].

Because treatment response remains heterogeneous, sample-size estimation and statistical design should explicitly account for biological variability. Conventional power calculations based solely on anticipated reductions in ambulatory BP may underestimate the sample size required to detect differences in hard clinical outcomes. Phenotype-enriched enrollment strategies, prespecified subgroup analyses, adaptive trial designs, and biomarker-guided recruitment may improve statistical efficiency while reducing heterogeneity among study populations [1,12,52,62,64].

Future investigations should continue to adopt rigorous randomized sham-controlled designs, standardized medication optimization protocols, objective assessment of medication adherence, blinded endpoint adjudication, and independent ABPM. Furthermore, development of reliable methods for procedural verification of successful denervation should become an important methodological objective. Objective confirmation of sympathetic nerve interruption would distinguish incomplete denervation from true biological non-response and substantially improve interpretation of future clinical trials [64,65,66,67,68]. Key recommendations for the design of future phenotype-guided RDN trials are summarized in Table 4.

Table 4. Recommendations for future phenotype-guided clinical trials of RDN beyond BP reduction.

Trial component	Recommended strategy	Rationale
Study population	Enroll phenotype-enriched patients with objective evidence of sympathetic overactivity rather than relying solely on resistant hypertension	Reduces biological heterogeneity and improves identification of responders
Patient selection	Integrate ABPM, autonomic biomarkers, target-organ phenotype, and renal artery anatomy	Supports precision medicine and mechanism-based enrollment
Trial design	Prospective, multicenter, randomized, sham-controlled studies	Minimizes bias and strengthens causal inference
Primary endpoints	Disease-specific clinical outcomes (e.g., MACE, HF hospitalization, AF recurrence, CKD progression) in addition to ambulatory blood pressure	Determines whether RDN modifies disease beyond BP reduction
Secondary endpoints	ABPM, HRV, resting heart rate, nocturnal BP, BP variability, renal function, LV remodeling, albuminuria, biomarkers, quality of life	Characterizes physiological mechanisms and target-organ responses
Autonomic assessment	Standardized measurement of clinically applicable autonomic biomarkers; incorporate MSNA or renal norepinephrine spillover in mechanistic substudies	Links autonomic modulation with clinical outcomes
Procedural quality	Standardized ablation protocols with objective verification of successful denervation when available	Reduces procedural variability and biological non-response
Follow-up duration	Minimum 24–36 mon with assessment of durability and late clinical outcomes	Allows evaluation of long-term disease modification
Statistical strategy	Prespecified phenotype-based subgroup analyses and multivariable prediction models	Identifies responder populations and reduces post hoc bias
Emerging technologies	Integrate imaging, computational modeling, and AI for patient selection and response prediction	Facilitates individualized treatment strategies
Clinical implementation	Validate responder algorithms externally before routine clinical adoption	Ensures reproducibility and generalizability

Recommendations are based on current mechanistic evidence, contemporary randomized trials, and expert consensus. The proposed framework is intended to guide future clinical research and should not be interpreted as established guideline recommendations.

ABPM, ambulatory blood pressure monitoring; MACE, major adverse cardiovascular events; HF, heart failure; AF, atrial fibrillation; CKD, chronic kidney disease; RDN, renal denervation; BP, blood pressure; HRV, heart rate variability; LV, left ventricular; MSNA, muscle sympathetic nerve activity; AI, artificial intelligence.

Ultimately, the future success of RDN should be judged not solely by its ability to lower BP but by its capacity to improve clinically meaningful CV, renal, and metabolic outcomes through targeted modulation of sympathetic pathophysiology. Achieving this objective will require phenotype-guided trial design, validated autonomic biomarkers, standardized procedural methodology, objective verification of successful denervation, and adequately powered outcome trials. Such an approach aligns closely with the principles of precision CV medicine and may ultimately establish RDN as a genuine disease-modifying therapy rather than simply an antihypertensive intervention [8,10,12,48,62,69,70,76].

Collectively, these developments support a gradual transition from a BP-centered treatment paradigm toward precision-guided autonomic intervention. Future clinical implementation of RDN will depend on validated responder phenotypes, objective procedural verification, and integration of multimodal clinical, imaging, anatomical, and biomarker data into individualized treatment strategies. AI and computational prediction models may further facilitate precision patient selection and procedural planning; however, these technologies remain investigational and require robust prospective validation. Ultimately, demonstration of durable improvements in clinically meaningful CV and renal outcomes will determine whether RDN evolves from an established antihypertensive therapy into a precision-based autonomic disease-modifying intervention.

LIMITATIONS OF THE CURRENT EVIDENCE AND PROPOSED FRAMEWORK

Despite the remarkable progress achieved in contemporary randomized sham-controlled trials, several important limitations continue to restrict interpretation of the current evidence and should be carefully considered when evaluating the broader therapeutic potential of RDN. Although consistent reductions in ambulatory BP have now been demonstrated across multiple studies, evidence supporting autonomic disease modification beyond BP lowering remains substantially less mature. Most available data originate from surrogate physiological endpoints, mechanistic investigations, or relatively small proof-of-concept studies rather than adequately powered clinical outcome trials [2,3,51,52,62,64].

A major limitation of the current literature is the absence of validated biomarkers capable of reliably identifying patients most likely to respond to RDN. While resting heart rate, HRV, ambulatory BP patterns, MSNA, renal norepinephrine spillover, and indices of target-organ injury all provide important physiological information, none has demonstrated sufficient diagnostic accuracy or prospective validation to support routine clinical decision-making. Consequently, the autonomic responder phenotype proposed in this review should be regarded as a conceptual framework intended to guide future investigation rather than a validated clinical algorithm [8,27,28,31,33,34,40,53,55,56,58].

Similarly, objective assessment of procedural success remains unavailable in routine clinical practice. Current RDN procedures rely predominantly on anatomical treatment strategies without direct confirmation that adequate interruption of renal sympathetic nerve signaling has been achieved. This limitation complicates interpretation of treatment non-response, as incomplete denervation cannot currently be distinguished from true biological resistance. Development of reliable intraprocedural biomarkers or physiological verification techniques therefore represents an important unmet need [64,65,66,67,68].

Another important limitation relates to the heterogeneity of published studies. Existing trials differ substantially with respect to patient selection criteria, antihypertensive medication regimens, device technology, procedural techniques, operator experience, endpoint definitions, and duration of follow-up. Such variability complicates direct comparison among studies and may partially explain differences in reported treatment response. Standardization of phenotyping strategies, procedural protocols, and clinical endpoints will therefore be essential for future evidence synthesis and guideline development [1,2,3,52].

Evidence supporting expansion of RDN beyond resistant hypertension also remains preliminary. Although encouraging mechanistic and early clinical data have been reported in conditions such as HF, AF, CKD, OSA, and metabolic disease, these observations are derived primarily from exploratory studies, secondary analyses, or small randomized trials. Whether autonomic modulation confers clinically meaningful benefits independent of BP reduction remains uncertain and requires confirmation in large, disease-specific outcome trials [10,12,13,71,72,73,74].

The proposed precision-based approach also has important limitations. Several candidate autonomic biomarkers—including HRV and resting heart rate—are influenced by age, physical conditioning, medications, diabetes mellitus, AF, and numerous other clinical variables, potentially limiting their specificity for sympathetic activation. Direct physiological measurements such as MSNA and renal norepinephrine spillover remain technically demanding, invasive, and largely confined to specialized research centers, restricting their applicability in routine clinical practice.

Finally, although AI and multimodal predictive modeling may eventually facilitate individualized patient selection, these approaches remain largely investigational. Robust external validation, prospective implementation studies, and demonstration of incremental clinical utility beyond conventional assessment will be required before computational prediction models can be incorporated into routine therapeutic decision-making [69,70].

Collectively, these limitations emphasize that the transition from an established antihypertensive intervention toward a precision-guided autonomic therapy has begun but is not yet complete. Future progress will depend on validation of responder phenotypes, development of objective procedural verification, standardization of clinical trial methodology, and demonstration of durable improvements in clinically meaningful CV and renal outcomes.

CONCLUSIONS

RDN has evolved from an experimental antihypertensive intervention into an established device-based therapy supported by consistent evidence from contemporary sham-controlled randomized trials. Beyond sustained BP reduction, accumulating mechanistic and clinical evidence suggests that interruption of renal sympathetic signaling may influence multiple biological pathways involved in CV, renal, and metabolic disease. However, current evidence supporting autonomic disease modification remains considerably less mature than the evidence supporting BP reduction and should therefore be interpreted with appropriate caution.

This review proposes a conceptual shift from evaluating RDN solely as a BP-lowering procedure toward considering it as a precision-based autonomic intervention. Rather than focusing exclusively on hypertension severity, future patient selection may benefit from identification of an autonomic responder phenotype integrating ambulatory BP characteristics, autonomic biomarkers, target-organ involvement, and anatomical suitability. Although this framework remains hypothetical and requires prospective validation, it provides a biologically grounded strategy for reducing responder heterogeneity and advancing individualized therapy.

Future progress in the field will depend on several critical developments, including validation of reliable autonomic biomarkers, objective intraprocedural confirmation of successful denervation, standardized procedural methodologies, and phenotype-enriched randomized clinical trials evaluating clinically meaningful CV, renal, and metabolic outcomes rather than BP reduction alone. Integration of computational modeling, multimodal phenotyping, and AI may further improve patient selection and procedural planning, ultimately facilitating implementation of precision CV medicine.

At present, RDN should continue to be regarded as an evidence-based treatment for appropriately selected patients with hypertension. Nevertheless, its broader role as a disease-modifying autonomic therapy remains investigational and requires confirmation through adequately powered outcome trials. Demonstrating durable improvements in CV events, renal protection, and patient-centered outcomes will determine whether RDN ultimately becomes not only an effective antihypertensive therapy but also a cornerstone of precision autonomic CV medicine.

Abbreviations

ABPM

ambulatory blood pressure monitoring

AF

atrial fibrillation

AI

artificial intelligence

BP

blood pressure

CKD

chronic kidney disease

CNS

central nervous system

CV

cardiovascular

eGFR

estimated glomerular filtration rate

HF

heart failure

HFpEF

heart failure with preserved ejection fraction

HRV

heart rate variability

HFrEF

heart failure with reduced ejection fraction

LV

left ventricular

LVH

left ventricular hypertrophy

MSNA

muscle sympathetic nerve activity

OSA

obstructive sleep apnea

RAAS

renin–angiotensin–aldosterone system

RDN

renal denervation

RMSSD

root mean square of successive RR interval differences

ROS

reactive oxygen species

SDNN

standard deviation of normal-to-normal RR intervals

SNS

sympathetic nervous system