The pulmonary veins were revealed to be the major source of atrial fibrillation (AF) two decades ago [1, 2, 3]. Since then, pulmonary vein isolation (PVI) has been established as a cornerstone in catheter ablation of AF. In cases of paroxysmal AF, the long-term success rate of catheter ablation has reached its pinnacle at 70–80% [4]. However, for persistent AF, this figure diminishes to a modest 60–70% [5]. Therefore, catheter ablations beyond PVI such as several ablation lesion sets targeting various anatomical structures of the atria other than the pulmonary veins, along with techniques to identify individual extra-pulmonary vein triggers of AF, have been developed in an effort to enhance the rate of AF freedom [6, 7, 8, 9]. Regrettably, none of these approaches have attained the status of a standard of care, unlike PVI. Hence, further research and refinement of strategies are imperative to advance the field of AF ablation and improve patient outcomes.

This article presents a contemporary review encompassing the rationale behind renal denervation (RDN) for AF management, the various tools involved, the efficacy and safety of the procedure, and the supporting evidence from relevant studies for a comprehensive understanding of the potential role of RDN as an adjunct therapy to PVI.

Human hearts possess a rich supply of autonomic nerves [10, 11, 12, 13], which govern various cardiac functions. The autonomic nervous system (ANS) has been identified as a key player in the pathophysiology of several arrhythmias, including AF. Modulating this system has demonstrated the potential to alter the electrophysiological properties of cardiac tissue, offering a promising avenue for arrhythmia control. Parasympathetic activation is associated with shortening of the atrial effective refractory period, making the atria susceptible to a reentry [14, 15, 16]. Conversely, stimulation of the sympathetic nervous system enhances intracellular calcium levels, thereby promoting a triggered activity and automaticity [11, 17]. The role of the cardiac ANS in initiating and maintaining AF has been extensively studied, leading to certain ablation approaches, such as an ablation targeting the ganglion plexi [18]. However, the outcomes of AF ablation using this approach have yielded conflicting results [19, 20, 21, 22]. Furthermore, it is crucial to acknowledge that vagal nerves also contain sympathetic components, as evidenced by the immunohistochemical studies [11]. This may explain the ambiguous outcomes observed in AF recurrence following the ganglionic plexus ablation [19] or Vein of Marshall ethanol infusion [23, 24]. The current technology of radiofrequency (RF) energy cannot selectively target either the parasympathetic or sympathetic components of the ANS in the heart, where both components are highly co-localized. A direct autonomic modulation at the cardiac tissue is further complicated by reinnervation and neuroplasticity, which enable nerve sprouting from surviving nerves after the ablation and constant remodeling of these nerves. This complex interplay underscores the need for a continued research and development in order to refine and optimize autonomic modulation as a therapeutic strategy for managing arrhythmias effectively.

The therapeutic effects of sympathetic denervation in controlling arrhythmias have been observed in the extra-cardiac sympathetic system. Adrenergic activation-induced metabolic remodeling plays a pivotal role in the initiation of acute AF and contributes to the progression of AF from a paroxysmal to persistent form [11, 14]. Rebalancing the activation of the ANS holds promise in potentially altering the course of AF progression. Addressing sympathetic activation has proven challenging, as it typically necessitates an invasive surgical procedure at the sympathetic trunk [10, 11, 25, 26]. However, an access to critical regions such as the stellate ganglion and T2$-$T4 sympathetic ganglion is not easily achievable, and this surgical approach is less favorable due to potential complications and debilitating side effects like hyperhidrosis and postural hypotension. Fortunately, current extracardiac neuromodulation modalities offer more appealing options due to their non or less-invasive nature. These modalities include transcutaneous tragus stimulation [27], stellate ganglion blockage [12, 28], baroreflex receptor therapy [29, 30], and renal denervation (RDN) [31, 32, 33, 34]. By virtue of their non or less-invasive nature, these approaches hold promise for managing sympathetic activation in AF patients more conveniently and with potentially fewer adverse effects.

The central sympathetic outflow is intricately regulated by afferent renal sympathetic signaling mediated through the posterior hypothalamus [11]. The presence of a dense and extensively interconnected network of sympathetic nerve fibers establishes a crucial link between the central nervous system and the kidneys, facilitated through the aortorenal ganglia [35]. This network presents a feasible target for percutaneous catheter ablation, offering a less invasive alternative to surgical approaches. RDN has garnered significant attention as a potential therapeutic approach for managing resistant hypertension [36, 37]. Considering this, RDN holds promise for providing both direct and indirect therapeutic effects on controlling AF, particularly when used in combination with PVI. It is plausible that RDN targeting the renal sympathetic nerves may exert a positive impact on a reduction of AF recurrence [31, 33, 38, 39, 40, 41].

The renal sympathetic nerves consist of both afferent and efferent arms, and they are found in the adventitia of the renal arteries [42, 43]. Efferent renal nerve mediates activity of renin-angiotensin-aldosterone system and regulates renal blood flow. Targeting the afferent arm of the renal sympathetic nerves is necessary to modulate the central sympathetic outflow to the peripheral organs. However, due to their close anatomical proximity in the adventitia of the renal arteries, percutaneous RDN procedures typically involve interrupting both arms of the renal sympathetic nerves inevitably. This simultaneous interruption of both arms is a practical challenge in achieving selective modulation but is currently the approach utilized in RDN procedures. Various approaches to ablate the renal nerve have been tested in the past [44], including ultrasound, RF energy, and drug infusion delivered through a catheter [45]. Among these options, percutaneous catheter ablation using RF energy appears to be the most feasible and widely used method. The procedure follows a workflow similar to a routine cardiac ablation for arrhythmia treatment.

The process of the RDN by RF catheter ablation typically involves an aortogram, which is performed using a pigtail catheter at the L1-2 vertebral level to visualize the renal artery (Fig. 1). Subsequently, a selective renal angiogram can be carried out using a diagnostic catheter (such as a left internal mammary [LIMA] catheter) to precisely identify the target location for the ablation (Fig. 2). To reduce the reliance on fluoroscopy during the procedure, a three-dimensional (3D) anatomical map of the renal artery and aorta can be constructed using impedance systems through a percutaneous catheter approach via the femoral artery (Fig. 3). Once the target site is identified, a conventional ablation catheter is positioned at the distal part of the renal artery to deliver RF energy application (Fig. 4, Ref. [46]). The RF energy is applied in a circumferential fashion while the catheter is withdrawn proximally (Fig. 3). The power settings for RF energy application typically range from 8 to 12 Watts, with each lesion receiving treatment for 1 to 2 minutes. The procedure is performed in the bilateral renal arteries and their branches.

It is worth noting that single electrode catheters are currently less favored for RDN than multi-electrode catheters due to the extensive neural network of small caliber vessels in the distal renal artery, which may not be well accommodated by larger size of catheters. To confirm the therapeutic effect of RDN, a comparison between baseline and post-ablation high-frequency stimulation tests of the afferent renal nerve is conducted. This involves observing the attenuated effect of an increase in blood pressure levels with stimulation, indicating a successful ablation outcome.

In terms of safety, certain criteria must be met to ensure the procedure is performed without complications. Specifically, the length of the renal artery should be at least 20 mm, and the diameter should be at least 4 mm to avoid any arterial damage [47, 48]. This can be estimated angiographically or more precisely measured using intravascular ultrasound imaging. Additionally, care should be taken to avoid any pathologic damage of the renal arteries, such as those displaying stenosis or calcification, as they may present higher risks for complications during the procedure.

Understanding the anatomy of the renal sympathetic nerve distribution is crucial for achieving excellent results of the RDN. The density of sympathetic nerves is highest in the proximal and mid-segments of the renal artery. However, the mean distance of these nerves from the artery is the lowest in the distal segment [42, 43]. Therefore, ablation at the distal part of the renal artery may be more effective approach for the RDN. Accessory arteries, which are also surrounded by sympathetic nerves, can be excellent targets for ablation as well. To ensure that these accessory arteries are not missed during the procedure, it is essential to observe fully-filled renal parenchyma with a contrast (Fig. 5). If any part of the renal parenchyma is unfilled, it may indicate the presence of an accessory artery. The high variation in renal nerve distribution poses a significant challenge in delivering RF energy precisely to reach the target nerves. The depth of the ablation lesion is typically around 2–4 mm [42, 49], which underscores the need for accurately-targeted delivery of RF energy during the procedure.

Considering the complex anatomy and distribution of the renal sympathetic nerves, careful planning and execution of the ablation procedure are critical for achieving successful outcomes in the RDN. Advanced imaging techniques and a thorough understanding of individual patient anatomy are instrumental in guiding the procedure to optimize the therapeutic effects of the RDN in managing AF and other conditions associated with sympathetic nervous system dysregulation.

There are 3 special systems that have been developed for RDN.

(1) Medtronic SYMPLICITY system (Fig. 6): The SYMPLICITY system utilizes the Symplicity Spyral™ multi-electrode (quadripolar) RDN catheter, which is a second-generation 6F catheter delivered over a 0.014 inches non-hydrophilic, flexible-tipped wire to the renal artery. The RF application begins distally and gradually moves proximally to the renal artery ostium. Adequate contact of the catheter on the arterial wall is verified by angiographic imaging obtained by a contrast injection from the catheter’s distal end and stable impedance values on each electrode, ensuring appropriate energy delivery throughout at least one respiratory cycle. This system allows for a selective deactivation of any electrode located in the unsuitable anatomy, such as the carina or areas with an arterial disease [50]. This system currently boasts the highest patient enrollment for clinical trials compared to other vendors (Table 1, Ref. [51, 52, 53, 54, 55, 56, 57]).

(2) Boston Scientific VESSIX system (Fig. 7): The VESSIX system [58] features a balloon catheter with an array of RF electrodes arranged to cover the renal nerves distributed around the renal arterial wall. This catheter is designed to maximize the efficiency of RDN by offering a remarkably short treatment duration of only 30 seconds per artery. The interruption of the blood flow by an occlusion of the renal artery with the balloon allows for the direct and precise delivery of energy to the targeted nerves. Non-contact electrodes are deactivated, and the system employs a bipolar energy distribution to ensure accurate targeting with very low energy doses ($\le$1 Watt).

(3) Abbott/SJM enligHTN system [59]: The enligHTN system [60] comprises an 8F multi-electrode basket catheter with four evenly-spaced electrodes that is designed to deliver faster and more precise RF energy to the renal nerves. Each treatment session requires an average of 90 seconds, leading to fewer catheter positioning steps. However, it is noted that this catheter is currently no longer commercially available due to a discontinuation in the product pipeline.

Potential complications related to RDN procedures include, but are not limited to, arterial stenosis (0.3%) and arterial rupture [61]. Previous studies have shown no significant arterial stenosis at 6 months post-ablation with the Medtronic SYMPLICITY Spyral catheter [62, 63]. The location of the electrodes is sensitive to subtle motion, making it crucial to avoid patient movement during the procedure, even during respiration. The system incorporates a sensitive temperature detector that automatically aborts RF energy delivery if any issues arise, prompting the operator to reimaging of the renal artery to rule out an arterial spasm. In cases of a reduced blood flow due to spastic artery, nitroglycerin is administered to resolve this issue [64]. Ablation on diseased arterial structures, such as fibromuscular dysplasia, existing arterial stenosis, atherosclerosis, or aneurysm, is prohibited to mitigate a potential risk of the complications. According to a recent comprehensive meta-analysis, the combined complication rate in the PVI and RDN group, pooled from 7 clinical studies, was at 6.32%. The combined rate of complications in the PVI alone group was also unexpectedly high at 11.8%. Notably, this concerning statistic was primarily attributed to vascular access complications, which may or may not be directly associated with RDN’s technology or tool. It is essential to highlight that all instances of renal artery stenosis (3/13) and renal artery dissection (3/13) stemmed from the HFIB-1 study in this analysis, where the Thermocool ablation catheter was employed without Food and Drug Administration (FDA) approval for RDN [65].

The first clinical evidence of the benefits of RDN as an adjunct therapy to PVI came from Pokushalov’s study [51]. In this small randomized study, a freedom from AF at 12 months was significantly higher in the RDN+PVI group (9/13 patients, 69%) than the PVI-only group (4/14 patients, 29%) (p = 0.033). This exciting finding sparked an interest in several subsequent clinical studies investigating RDN’s role as an adjunct therapy to conventional PVI.

The Evaluate Renal Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE AF) trial stands as a landmark trial that showcases the efficacy of RDN as an adjunct therapy to AF ablation [52]. In patients with poorly controlled hypertension and paroxysmal AF, the combination of RDN and AF ablation significantly improved an AF freedom at 1 year when compared with AF ablation without RDN (71.4% vs. 57.8%, hazard ratio of 0.61, confidence interval of 0.41–0.9, p = 0.011), with similar complication rates. Various small randomized controlled trials have also been conducted, showing favorable outcomes [37, 40, 66, 67]. A meta-analysis by Ukena et al. [68] included 689 AF patients with poorly controlled hypertension (those who failed to control blood pressure with three antihypertensive medications) from 5 out of the 6 included studies. The results of this meta-analysis demonstrated significant reduction of the blood pressure as well as AF recurrence (mean odds ratio of 0.43 with a 95% confidence interval) in patients treated with both RDN and PVI (either RF or cryoablation) compared to PVI alone. While the meta-analysis and its subsequent updates confirmed these observations, it is essential to consider the influence of the results derived from large randomized controlled trials like ERADICATE AF. Table 1 compiles essential randomized controlled trials pertinent to the outcomes of RDN in the context of AF suppression.

Several ongoing studies are currently adding more knowledge to this field. The Trial to Evaluate Renal Artery Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE AF II) aims to test the hypothesis that combining PVI with RDN can provide a long-term antiarrhythmic effect compared to PVI alone for patients with symptomatic persistent AF without hypertension or with well-controlled hypertension. This multi-center, single-blinded, randomized controlled trial requires all subjects to have a loop recorder implanted for a precise AF burden calculation. The positive results of this study would have a potential to establish RDN as an adjunct therapy to AF ablation, with the possibility of becoming a standard care for persistent AF patients.

Indeed, the effectiveness and cost-effectiveness of RDN as a treatment approach for resistant hypertension have been a subject of numerous studies, and their mixed results lead to ongoing debates among scholars. Some studies have shown that RDN can be a cost-effective approach [69, 70], while others have not found any significant benefits in blood pressure reduction from RDN. One pivotal study, the SYMPLICITY-3 trial conducted in 2014 [71], demonstrated no significant benefit in blood pressure reduction from RDN. However, it is crucial to note that this trial used the first-generation ablation catheter with a single electrode, which did not allow for a verification of contact between the electrode and the arterial wall. Subsequent clinical studies utilizing the second-generation devices, such as the DENERHTN trial [72], the Spyral HTN-ON MED trial [73, 74], and the Spyral HTN-OFF MED trial [75, 76], have shown promising results with a significant blood pressure reduction. These second-generation devices have offered more advanced features and improvements in the ablation catheter technology.

The exact regimen of the ablation, including the number of lesions, distance between lesions, amount of RF energy delivery, and exposure time, has not been conclusively supported by previous studies. As a result, the therapeutic effect of RDN on a blood pressure control remains a topic of interest and feasibility for future researches. It is important to consider that the effectiveness of RDN may be influenced by factors such as the experience and skill of the practitioners performing the procedure and the careful patient selection. As more researches are conducted with advanced ablation catheter technologies and improved techniques, the potential benefits of RDN for resistant hypertension may become more evident and established.

In summary, RDN has shown promise as an effective therapeutic modality for AF treatment. While it is not yet a standard of care, RDN’s percutaneous nature and robust safety data have led to a growing number of clinical trials in different patient populations. These trials are worth monitoring for further insights. Continued research and data collection on RDN’s long-term effects on AF freedom and its application in various patient populations, including non-hypertensive patients, will help solidify its role as an adjunct therapy to PVI in AF ablation. With an increasing body of clinical evidence supporting the positive outcomes of RDN in various stages of AF across different patient populations, percutaneous catheter-based RDN emerges as a highly promising intervention to be conveniently administered during the same index procedure as standard pulmonary vein isolation by cardiac electrophysiologists.

AF, atrial fibrillation; ANS, autonomic nervous system; CKD, chronic kidney disease; PVI, pulmonary vein isolation; RDN, renal denervation; RF, radiofrequency.

KA performed literature search and wrote manuscript. TY has participated in the conception of the work and the acquisition, analysis, and interpretation of data for the work. TY provided help and advice on direction of discussion and details in manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research received no external funding.

The authors declare no conflict of interest. Takumi Yamada is serving as Guest Editor of this journal. We declare that Takumi Yamada had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Buddhadeb Dawn.