# Cardiac Neuromodulation for Ventricular Arrhythmias: Current State and Future Perspectives. A comprehensive review

Pierre Groussin, Donovan Decaudin, Melvyn Dezecot, Thomas Marc, Nathalie Behar, Dominique Pavin, Christophe Leclercq, Philippe Mabo, Karim Benali, Raphaël P Martins

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Pierre Groussin, Donovan Decaudin, Melvyn Dezecot, Thomas Marc, Nathalie Behar, et al., Cardiac Neuromodulation for Ventricular Arrhythmias: Current State and Future Perspectives. A comprehensive review. Trends in Cardiovascular Medicine, 2025, 35 (7), pp.452-465. 10.1016/j.tcm.2025.05.001. hal-05099004

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# Cardiac neuromodulation for ventricular arrhythmias: Current state and future perspectives. A comprehensive review

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Pierre Groussin<sup>a,*</sup>, Donovan Decaudin<sup>a</sup>, Melvyn Dezecot<sup>a</sup>, Thomas Marc<sup>a</sup>, Nathalie Behar<sup>a</sup>, Dominique Pavin<sup>a</sup>, Christophe Leclercq<sup>a</sup>, Philippe Mabo<sup>a</sup>, Karim Benali<sup>b</sup>, Raphaël P. Martins<sup>a</sup>

## ARTICLE INFO

### Keywords:

* Arrhythmia ventricular
* Electrical storm
* Cardiac neuromodulation
* Ventricular tachycardia

## ABSTRACT

Electrical storm represents an urgent challenge in electrophysiology. Despite the use of antiarrhythmic medications and catheter ablation, refractory ventricular arrhythmias may persist, prompting the use of neuromodulation. This approach has evolved over the years, facing initial challenges owing to the intricacies of the autonomic nervous system. Animal studies have significantly enhanced our understanding of this system, paving the way for human studies on sympathetic modulation, which gained momentum in the early 2000s and expanded notably in cardiology in the 2010s. Presently, a variety of techniques coexist and offer diverse alternatives. Additionally, there are promising avenues for development that are primarily explored in animal models. This review aims to shed light on the diverse approaches currently available in this field.

© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

## Key points

Cardiac sympathetic modulation is an evolving therapeutic option for managing refractory ventricular arrhythmias.

The four primary techniques—thoracic epidural anesthesia, percutaneous stellate ganglion blockade, surgical sympathetic denervation, and renal sympathetic denervation—target different components of the sympathetic nervous system.

Non-invasive neuromodulation strategies are emerging as potential alternatives to invasive techniques, though robust evidence supporting their efficacy is still lacking.

A personalized, multimodal approach is essential to optimize treatment, tailoring neuromodulation strategies to the patient's clinical profile and underlying arrhythmic substrate.

Future developments may integrate neuromodulation with advanced imaging and personalized medicine to enhance

outcomes and improve long-term management of ventricular arrhythmias.

## Introduction

The term "electrical storm" introduced in the 1990s is defined by the occurrence of at least three sustained ventricular arrhythmias (VA) (ventricular tachycardia (VT) or ventricular fibrillation (VF) over a 24-hour period, separated by an interval of at least 5 min [1]. This phenomenon affects 9-28 % of patients with implanted cardioverter-defibrillators for secondary prevention, compared to 1-4 % in those implanted for primary prevention [2]. Electrical storm represents a pivotal point in disease progression, marked by a dismal prognosis as reflected by a one-year mortality rate of up to 34 % in some studies [3]. The 3 components of the Coumel's triangle, arrhythmogenic substrate, triggering factors and modulating factors, play a primary role in electrical stormogenesis [4]. The autonomic nervous system is one of the main modulators involved, and sympathetic modulation has gradually emerged as a therapeutic approach for VA refractory to medical treatment (including antiarrhythmic drugs, correction of precipitating factors, and light to moderate sedation) and catheter ablation. In this con-

**Abbreviations:** PSGB, percutaneous stellate ganglion blockade; RSD, renal sympathetic denervation; SSD, surgical sympathetic denervation; TEA, thoracic epidural anesthesia; VA, ventricular arrhythmia; VF, ventricular fibrillation; VT, ventricular tachycardia.

E-mail address: pierre.groussin@chu-rennes.fr (P. Groussin).

<footnote><sup>a</sup> Univ Rennes, CHU Rennes, INSERM, LTSI – UMR 1099, F-35000 Rennes, France</footnote>

<footnote><sup>b</sup> CHU de Saint-Étienne, 42000 Saint-Étienne, France</footnote>

<footnote>* Corresponding author at: Département de Cardiologie et Maladies Vasculaires, CHU de Rennes, Cedex 35033, Rennes, France.</footnote>
text, it offers a means of achieving stabilization while potentially avoiding more invasive interventions such as general anesthesia or mechanical circulatory support, especially in fragile or unstable patients. Therefore, a comprehensive investigation of this vast and intricate system is imperative. This literature review, following an overview of the anatomy of the autonomic nervous system and its link to VAs, explores various techniques for performing cardiac neuromodulation in refractory VA.

## The autonomic nervous system

The autonomic nervous system is a part of the nervous system associated with internal organs and operates independently of voluntary control. It can be influenced by information from peripheral receptors, such as baroreceptors, chemoreceptors, and proprioceptors, leading to variations in heart rate, blood pressure, and electrical conduction. The autonomic nervous system comprises a parasympathetic division, primarily serving as a "brake," and a sympathetic division, exerting a predominantly "stimulatory" effect. Theoretically, these two divisions act in harmony to ensure homeostasis by regulating various cardiac physiological functions. However, in a patient with underlying heart disease, there may be inhibition of the parasympathetic system and pronounced hyperactivation of the sympathetic system.

### Extrinsic sympathetic system

In the efferent pathway, although influenced by various brain regions, notably the brainstem, the first preganglionic neuron originates from the intermediolateral horn of the spinal cord. It exits the spinal cord via the anterior roots, enters the spinal nerves, traverses the anterior rami, and travels through the white rami communicantes to reach the autonomic ganglia. Synaptic transmission then occurs at the level of the autonomic ganglia between this preganglionic neuron and a second postganglionic neuron that innervates the heart [5]. These ganglia include the upper cervical ganglia (C1-C3), middle cervical ganglia (C4-C6), stellate ganglion (C7-C8 and T1-T2), and thoracic ganglia (T3-T6). Postganglionic neurons, also known as sympathetic cardiac nerves (upper, middle, and lower cervical/thoracic), may synapse either directly with the myocardium or with ganglion plexuses in the epicardial layer [6].

The neurotransmitter for this system is norepinephrine, which primarily acts on beta-adrenergic and alpha-adrenergic receptors. When norepinephrine binds to its receptors, it activates adenylate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate. The latter activates protein kinase A, which, through a phosphorylation mechanism, facilitates a transient increase in calcium load that may promote arrhythmogenesis [7]. There is a descending gradient of nerve density from the base to the apex of the ventricle. The left sympathetic chain predominates in cardiac innervation, with studies suggesting increased VF threshold and protection against ischemic VA for left stellate ganglion blockade, while initially the opposite effect was noted in right blockade although recent studies question this [8]. The stellate ganglia affects most cardiac regions, with the right side influencing the posterior right ventricular part and the left side predominantly affecting the anterior and apical parts of the left ventricle [9]. It is noteworthy that another sympathetic stimulation pathway exists through the adrenal medulla glands, leading to the release of catecholamines into the bloodstream, which interact with myocardial receptors.

### Parasympathetic extrinsic system

Preganglionic parasympathetic efferent neurons originate from the brainstem (nucleus ambiguus and dorsal motor nucleus) and

travel via the vagus nerve to synapse in epicardial cardiac ganglia. The neurotransmitter acetylcholine primarily acts on the muscarinic receptors, with stronger effects in the atria due to a higher density of cholinergic receptors. The vagus also carries afferent and adrenergic fibers, which may contribute to arrhythmia initiation.

### Intrinsic autonomic nervous system

In the epicardial fat, a mingling of multiple sympathetic and parasympathetic neurons is interconnected and organized as ganglion plexuses are present. The intrinsic nervous system acts independently or in conjunction with the extrinsic nervous system.

## Link between autonomic nervous system and ventricular arrhythmia

The autonomic nervous system plays a crucial role in triggering VA. Its activation is heightened by stress and electrical shocks, creating a detrimental cycle in patients experiencing recurrent rhythmic events. Regarding the specific link between the autonomic nervous system and VA, it is essential to understand that sympathetic system activation, in addition to releasing cardiac norepinephrine, can, during elevated sympathetic drive, release sympathetic co-transmitters such as neuropeptide Y, which may affect the efficacy of beta-blockers [10]. Neuropeptide Y shortens action potential duration and refractory period, making early afterdepolarizations less likely—although early afterdepolarizations can still occur in the setting of calcium overload through L-type calcium channel reactivation, particularly via Ca2+/calmodulin-dependent protein kinase II activation. In contrast, neuropeptide Y promotes delayed afterdepolarizations by activating Ca2+/calmodulin-dependent protein kinase II, leading to ryanodine receptor dysfunction and spontaneous calcium release events that can trigger VAs [11]. These effects are accentuated in cardiac diseases with cardiac neuronal remodeling.

Cardiac neuronal remodeling in ischemic cardiomyopathy is typically initiated by myocardial lesions, which often occur in an inflammatory context. These lesions lead to sympathetic axonal damage, resulting in initial denervation as early as 20 min after coronary occlusion, affecting both infarcted and theoretically healthy peripheral zones. Some regions remain denervated, developing hypersensitivity to catecholamines, seemingly due to the lack of uptake by absent nerve endings, which fail to buffer the local concentration of circulating catecholamines at the myocyte level [12]. In contrast, other regions are reinnervated by nerve growth factors, predominantly in the border zones of the infarcted territory. This reinnervation creates an uneven distribution of sympathetic efferent fibers, contributing to ventricular repolarization dispersion. Remodeling of the stellate ganglia also occurs and is characterized by significant neuronal enlargement and increased synaptic density, further exacerbating this phenomenon [13].

In 2012, Vaseghi et al. studied recovery intervals in the anteroapical region of the left ventricle in a patient with ischemic cardiomyopathy, before and after isoproterenol injection. The change in the activation–recovery interval was more pronounced in normal and infarcted areas than in border zones, which is explained by a lower density of β-adrenergic receptors in these transitional regions. This suggests that the most innervated areas paradoxically exhibit reduced β-receptor density compared to denervated regions [14]. Such imbalance contributes to the formation of a repolarization gradient that promotes ventricular arrhythmias [15].

This imbalance—combining hypersensitive denervated zones and hyperactive reinnervated regions—represents a key target for therapeutic neuromodulation. Techniques such as percutaneous stellate ganglion block (PSGB) or thoracic epidural anesthesia (TEA) act on innervated myocardial regions, particularly border zones,
which are often involved in arrhythmia initiation. By reducing ex-
citability in these areas, regional neuromodulation may help limit
arrhythmic risk. Conversely, denervated regions—characterized by
β-receptor upregulation and impaired norepinephrine reuptake—
become highly sensitive to circulating catecholamines. In such
cases, systemic approaches such as renal sympathetic denervation
(RSD) may help reduce overall sympathetic tone and protect these
vulnerable areas.

Sympathetic modulation techniques

Currently, four major techniques are used for sympathetic modulation (Tables 1 and 2, Fig. 1): TEA, PSGB, surgical sympathectomy denervation (SSD), and RSD. Each technique is described below. Notably, combinations of these techniques have been reported in some case series [16,17].

Thoracic epidural anesthesia – Fig. 2

TEA is an invasive technique that is performed with the pa-
tient in the lateral decubitus position. After ensuring proper asep-
sis, an 18 G epidural needle is inserted between the T1-T2 or T2-
T3 vertebrae using the loss-of-resistance technique. Once the ab-
sence of cerebrospinal fluid and blood is confirmed by aspiration,
an epidural catheter is advanced 5 cm beyond the needle tip into
the epidural space and secured in place. Subsequent aspiration is
performed to exclude intrathecal and intravascular catheter place-
ment. Anesthetic agents, such as bupivacaine, lidocaine, or a com-

bination of both, are then injected as a bolus, followed by a po-
tential continuous infusion. This procedure achieves a sympathetic
blockade from T1 to T4. This technique allows for an immediate
onset of action, a short duration of effect, and the possibility of
titration. However, accurate titration remains challenging because
of the absence of easily measurable markers apart from arrhythmia
control. Notably, TEA has not been shown to significantly affect pa-
rameters such as the heart rate, mean arterial pressure, or cardiac
index [18]. Patients on anticoagulants, dual antiplatelet therapy, or
active infections are contraindicated to this procedure.

The antiarrhythmic effects of TEA were first documented in 1988 in a post-myocardial infarction rodent model [19]. The study demonstrated a significant reduction in ventricular arrhythmias through an increased VF threshold compared with controls. Similarly, a porcine model of induced infarction revealed a prolonged ventricular refractory period and increased parasympathetic activity due to disruption of sympathetic afferent fiber neurotransmission [20]. The first clinical case of refractory VA successfully treated with TEA in a patient with ischemic heart disease was reported more than a decade ago [21]. Since then, several case reports [22–24] have consistently demonstrated favorable outcomes of TEA in reducing arrhythmic episodes. In 2010, Bourke et al. [25] published the first retrospective series assessing the efficacy of left SSD and TEA in managing electrical storms. When analyzing TEA alone, six of eight patients achieved a reduction of >80 % in arrhythmia burden post-procedure, with no reported adverse effects. These promising findings were corroborated by a 2017 retrospective study of 11 patients with refractory VT. The study revealed that five patients experienced a complete response, with total suppression of VT episodes within 48 h, while one patient had a partial response with an 80–99 % reduction in episodes. No complications were observed. Interestingly, all four patients who underwent deep sedation demonstrated a complete response to TEA [26].

Thus, TEA represents a potentially valuable short-term alter-
native to prolonged deep sedation or intubation, particularly for
hemodynamically unstable patients awaiting definitive treatments,
such as ablation or cardiac transplantation or stereotactic radio-
therapy.

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Schematic representation of four historical sympathetic modulation techniques. Adapted with permission from Nguyen et al. [7].

ATI: angiotensin I, ATII: angiotensin II, CSD: cardiac sympathetic denervation, NE: norepinephrine, RDN: renal sympathetic denervation SGB: stellate ganglion blockade, TEA: thoracic epidural anesthesia.</figcaption></figure>

Percutaneous stellate ganglion block – Fig. 3

PSGB is a minimally invasive technique performed under ultra-
sound guidance alone, in combination with fluoroscopy, or without
imaging support and can be performed in the patient's room with
no need for sedation. Typically, there are two possible approaches:
an anterior approach (possible without imaging) and a lateral ap-
proach, depending on each center's experience. It is crucial, espe-
cially in anterior approaches, to identify the transverse process of
C6, also known as the Chassaignac tubercle. The patient initially
lies supine with the head turned towards the contralateral should-
der. Following a negative aspiration test, a bolus of the local anes-
thetic is injected with or without subsequent continuous infusion
(recent studies suggest that continuous infusion yields superior ef-
ficacy compared with a single bolus) [27]. The patient must then
remain semi-seated for 2 hours to allow gravitational distribution
of the anesthetic along the sympathetic tract. The blockade is tran-
sient and is primarily linked to the pharmacokinetics of the anes-
thetic. However, it has been hypothesized that the local anesthetic
may also "reset" the stellate ganglion, leading to a prolonged re-
duction in sympathetic stimulation responsible for VA. The effec-
tiveness of the procedure is typically confirmed by the appearance
of ipsilateral Horner syndrome, although its presence is inconsis-
tent and not correlated with the antiarrhythmic effect. Rare com-
plications such as hematoma, pneumothorax, and laryngeal nerve
blocks have been described [28]. Discontinuation of anticoagula-
tion therapy is not mandatory.
<table><caption>**Table 1**
Clinical Studies on Sympathetic Modulation for Treatment of Ventricular Arrhythmias in Structural Heart Disease.</caption><thead><tr><th>Modality</th><th>Year</th><th>Citation</th><th>Study Type</th><th>Number</th><th>Etiology of CMI</th><th>Type of VT</th><th>Follow-up</th><th>Main findings</th></tr></thead><tbody><tr><td rowspan="2">Thoracic Epidural Anesthesia</td><td>2010</td><td>Bourke et al</td><td>Retrospective</td><td>8</td><td>50 % ICM; 50 % NICM%</td><td>62 % MVT; 38 % PMVT</td><td>48 hours</td><td>6 out of 8 patients experienced a reduction of >80 % in arrhythmia burden following the procedure</td></tr><tr><td>2017</td><td>H Do et al</td><td>Retrospective</td><td>11</td><td>55 % ICM; 45 % NICM</td><td>72 % MVT; 28 % PMVT</td><td>48 hours</td><td>6 out of 11 patients experienced a reduction of >80 % in arrhythmia burden following the procedure</td></tr><tr><td rowspan="6">Percutaneous Stellate Ganglion Block</td><td>2016</td><td>Garcia-Moran et al</td><td>Case series</td><td>8</td><td>37.5 % ICM; 50 % NICM; 12.5 % other</td><td>100 % PMVT</td><td>24 hours</td><td>In 6 patients, the number of arrhythmia episodes declined during the first 24 hours after the procedure</td></tr><tr><td>2017</td><td>Fudim et al</td><td>Systematic review, meta-analysis</td><td>35</td><td>51.4 % ICM; 28.6 % NICM, 20 % others</td><td>37.1 % MVT; 74.3 % PMVT</td><td>24 hours</td><td>Improved short-term control of the VA burden and reduced need for external or internal defibrillation</td></tr><tr><td>2017</td><td>Meng et al</td><td>Systematic review, meta-analysis</td><td>38</td><td>45 % ICM; 18 % NICM; 37 % others</td><td>10.5 % MVT; 31.6 % PMVT; 18.4 % VF; 39.5 % mixed VT / VF</td><td>6 - 28 days</td><td>Significant reduction in both the episodes of VA, and number of shocks in patients with ES after PSGB</td></tr><tr><td>2019</td><td>Thian et al</td><td>Retrospective, monocenter</td><td>30</td><td>57 % ICM; 33 % NICM, 10 % others</td><td>40 % MVT; 10 % VF; 50 % mixed VT / VF</td><td>72 hours</td><td>After SGB, 50 % of patients with ES were free of VA, and VA episodes were reduced by 92 % at 72 hours</td></tr><tr><td>2020</td><td>Fudim et al</td><td>Retrospective, monocenter</td><td>20</td><td>50 % ICM; 50 % NICM</td><td>50 % MVT; 50 % PMVT</td><td>48 hours</td><td>Reduced burden of arrhythmia and defibrillation events 24 and 48 h after nerve blockade</td></tr><tr><td>2021</td><td>Savastano et al</td><td>Prospective, monocenter</td><td>11</td><td>73 % ICM; 27 % NICM</td><td>27.8 % MVT, 16.7 % VF, mixed VT / VF 55.6 %</td><td>24 hours</td><td>Arrhythmic burden 24 h before the first PSGB and after the last procedure showed a significant reduction [7 vs. 1, P = 0.002]</td></tr><tr><td>2021</td><td>Reinertsen et al</td><td>Retrospective, monocenter</td><td>13</td><td>46 % ICM; 54 % NICM</td><td>Not reported</td><td>96 hours</td><td>Significant reduction in VA and defibrillation episodes, which persisted for 96 hours</td></tr><tr><td>2023</td><td>Jiravsky et al</td><td>Prospective, monocenter</td><td>59</td><td>60 % ICM; 40 % NICM</td><td>72.9 % MVT, 12.9 % PMVT, 11.4 % VF, 2.9 % mixed VT / VF</td><td>>48 hours</td><td>Reduction in ICD shocks and ATPs at 48 hours reached 87 % and 65.9 %, respectively</td></tr><tr><td>2024</td><td>Dusi et al</td><td>Multicenter</td><td>26</td><td>54 % ICM; 46 % NICM</td><td>56 % MVT; 22 % VF / PMVT; 22 % mixed VT / VF</td><td>12 hours</td><td>13/26 patients (50 %) had a complete response, and an overall clinical benefit was observed in 24/26 patients (92 %).</td></tr><tr><td>2024</td><td>Chouairi et al</td><td>Retrospective, multicenter</td><td>117</td><td>52.1 % ICM; 50.4 % NICM; 42.7 % others</td><td>70.1 % MVT; 41 % PMVT, 31.6 % VF</td><td>48 hours</td><td>74 (63.2 %) patients responded to PSGB (had reduction of ≥50 % in 24-hour VT/VF burden)</td></tr><tr><td>2024</td><td>Savastano et al</td><td>Prospective, multicenter</td><td>131</td><td>56.5 % ICM, 28.2 % NICM, 15.3 % others</td><td>64.1 % MVT; 19 % VF; 16.8 % mixed VT / VF</td><td>12 hours</td><td>106 (92.2 %) showed a reduction in the number of treated episodes of ≥50 % in the 12 h after the procedures</td></tr></tbody></table>

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<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Modality</th><th>Year</th><th>Citation</th><th>Study Type</th><th>Number</th><th>Etiology of CMI</th><th>Type of VT</th><th>Follow-up</th><th>Main findings</th></tr></thead><tbody><tr><td rowspan="10">Surgical sympathetic Denervation</td><td>2010</td><td>Bourke et al</td><td>Retrospective</td><td>9</td><td>22 % ICM; 78 % NICM</td><td>78 % MVT; 22 % PVMT</td><td>6.2 ± 4.6 months</td><td>33 % ICD shock-free post denervation. 22 % decreased VA cardiac events. 22 % mortality. 66 % ICD shock-free post denervation. 33 % mortality (within 1 month)</td></tr><tr><td>2012</td><td>Ajijola et al</td><td>Retrospective</td><td>6</td><td>34 % ICM; 66 % NICM</td><td>83 % MVT; 17 % PMVT</td><td>120±69 days</td><td>30.7 % ICD shock-free post denervation. 12 % Mortality</td></tr><tr><td>2014</td><td>Methangkool et al</td><td>Retrospective</td><td>26</td><td>23 % ICM; 62 % NICM; 15 % other</td><td>Not reported</td><td>1 year</td><td>57.1 % ICD shock-free post denervation. 14.3 % Mortality.</td></tr><tr><td>2016</td><td>Saenz et al</td><td>Retrospective</td><td>7</td><td>100 % NICM</td><td>100 % MVT</td><td>7 months</td><td>28.6 % ICD shock-free post denervation. 28.6 % mortality (within 48 hours).</td></tr><tr><td>2016</td><td>Prabhu et al</td><td>Retrospective</td><td>7</td><td>78 % ICM; 22 % NICM</td><td>55.5 % MVT; 44.5 % PVT / VF</td><td>33±12 months</td><td>71.4 % Recurrence of VA cardiac events</td></tr><tr><td>2017</td><td>Vaseghi et al</td><td>Retrospective, multicenter</td><td>121</td><td>27 % ICM; NICM 71 %; 2 % mixed</td><td>72.3 % MVT; 22.7 % PMVT</td><td>1.5 ± 1,4 years</td><td>58 % free of VA/ICD shock at 1 year, 49 % at mean 1.5 year; 76.2 % free of death/transplant at 1 year</td></tr><tr><td>2018</td><td>Gardona-Guarache et al</td><td>Retrospective</td><td>6</td><td>83 % ICM; 17 % NICM</td><td>83 % VF; 17 % mixed MVT / VF</td><td>6 months</td><td>100 % ICD shock-free post denervation; 0 % mortality.</td></tr><tr><td>2018</td><td>Richardson et al</td><td>Case series</td><td>7</td><td>28.5 % ICM; 43 % NICM; 28.5 % no cardiopathy</td><td>57 % MVT; 29 % VF; 14 % mixed VT / VF</td><td>7 ± 5 months</td><td>100 % ICD shock-free post denervation; 14.3 % transplanted; no sustained VA in follow-up</td></tr><tr><td>2019</td><td>Okada et al</td><td>Case series, monocenter</td><td>5</td><td>100 % NICM</td><td>Not reported</td><td>26 months</td><td>100 % ICD shock-free post denervation; 0 % mortality; 60 % no recurrence of sustained VA</td></tr><tr><td>2019</td><td>Assis et al</td><td>Case series</td><td>8</td><td>100 % NICM</td><td>Not reported</td><td>1.9 ± 0.9 years</td><td>63 % ICD shock-free post denervation; 0 % mortality</td></tr><tr><td>2019</td><td>Cai et al</td><td>Case series, monocenter</td><td>19</td><td>21.1 % ICM; 78.9 % NICM</td><td>Not reported</td><td>2.07 years</td><td>47 % ICD shock-free post denervation; 21 % mortality mean follow-up 2.8 yrs</td></tr><tr><td>2019</td><td>Tellez et al</td><td>Case series, monocenter</td><td>20</td><td>35 % ICM; 65 % NICM</td><td>90 % MVT; 10 % mixed VT / VF</td><td>9.8 ± 9.5 weeks</td><td>90 % ICD shock-free post denervation; 5 % mortality</td></tr><tr><td>2020</td><td>Yalin et al</td><td>Retrospective, monocenter</td><td>10</td><td>100 % NICM</td><td>Not reported</td><td>0.84 years</td><td>60 % ICD shock-free post denervation; 20 % mortality (within 1 month)</td></tr><tr><td>2020</td><td>Murtaza et al</td><td>Meta-analysis</td><td>311</td><td>ICM; NICM; channelopathy</td><td>Not reported</td><td>15±10.7 months</td><td>Pooled rate of freedom from VT after SSD in all causes of arrhythmia: 60 % / in ICM and NICM: 50 %</td></tr><tr><td>2021</td><td>Chihara et al</td><td>Systematic review, meta-analysis</td><td>275</td><td>ICM; NICM</td><td>Not reported</td><td>Mean 16 months</td><td>52.4 % were alive and free of ICD shocks and heart transplantation at a mean follow-up of 1.38 years after undergoing left or bilateral SSD. ICD shock-free rate of 62.2 %</td></tr><tr><td>2021</td><td>Barwad et al</td><td>Retrospective</td><td>65</td><td>46 % ICM; 54 % NICM</td><td>87.7 % MVT; 12.3 % PMVT</td><td>Mean 27±24 months</td><td>Significant reduction in ICD discharges post-SSD, with freedom from shock at 2 years being 69.2 %.</td></tr></tbody></table>

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<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Modality</th><th>Year</th><th>Citation</th><th>Study Type</th><th>Number</th><th>Etiology of CMI</th><th>Type of VT</th><th>Follow-up</th><th>Main findings</th></tr></thead><tbody><tr><td rowspan="10">Renal Sympathetic Denervation</td><td>2014</td><td>Remo et al</td><td>Retrospective, monocenter</td><td>4</td><td>50 % ICM; 50 % NICM</td><td>100 % MVT</td><td>8.8 ± 2.6 months</td><td>VT episodes decreased from 11.0 ± 4.2 (5.0-14.0) during the month before ablation to 0.3 ± 0.1 (0.2-0.4) per month after</td></tr><tr><td>2015</td><td>Armaganijan et al</td><td>Prospective, monocenter</td><td>10</td><td>80 % NICM; 20 % ICM</td><td>50 % MVT; 50 % mixed PMVT/VF</td><td>6 months (range 18 - 180)</td><td>Reduced arrhythmic burden, number of ATP ant shocks with no procedure-related complications</td></tr><tr><td>2016</td><td>Evranos et al</td><td>Retrospective, propensity score</td><td>16</td><td>38 % NICM; 62 % ICM</td><td>Not reported</td><td>15 months (range 6-20)</td><td>Significant decrease in burden VT / VF, ATP and shocks therapies</td></tr><tr><td>2016</td><td>Ukena et al</td><td>Retrospective, monocenter</td><td>13</td><td>54 % ICM; 46 % NICM</td><td>54 % MVT; 46 % PMVT; 62 % VF</td><td>12 months</td><td>Number of VA was significantly reduced following RSD</td></tr><tr><td>2018</td><td>Jiang et al</td><td>Prospective, monocenter</td><td>8</td><td>12.5 % ICM; 87.5 % NICM</td><td>Not reported</td><td>15 months (range 6-30)</td><td>Median VA episodes per month were significantly reduced from 3.17 (range 0.33-15.33) to 0.10 (range 0-5.83) after RSD</td></tr><tr><td>2020</td><td>Bradfield et al</td><td>Retrospective, monocenter</td><td>10</td><td>10 % ICM; 90 % NICM</td><td>70 % MVT; 30 % PMVT</td><td>28 months</td><td>Decrease in all implantable cardioverter-defibrillator therapies</td></tr><tr><td>2021</td><td>Garg et al</td><td>Systematic review, meta-analysis</td><td>51</td><td>56.9 % ICM; 43.1 % NICM</td><td>Not reported</td><td>Several months</td><td>Significant reduction in mean VA episodes (p &lt; .01), shocks (p &lt; .01) and ATP (p &lt; .01) following RSD</td></tr><tr><td>2021</td><td>Hawson et al</td><td>Systematic review, meta-analysis</td><td>121</td><td>55 % ICM; 45 % NICM</td><td>Not reported</td><td>Several months</td><td>RSD also reduced the number of VA episodes (p &lt; 0.001), antitachycardia pacing episodes (p = 0.002), and shocks (p = 0.002).</td></tr><tr><td>Stellate ganglion ablation using radiofrequency</td><td>2023</td><td>Hygriv Rao et al</td><td>Case series</td><td>6</td><td>33 % ICM; 50 % NICM; 17 % other</td><td>33 % MVT; 17 % VF; 50 % mixed VF / PMVT</td><td>Mean 22±8 months</td><td>All patients were rescued from ES and survived to discharge. At a mean follow-up of 22 ± 8 months, two patients received appropriate shocks for VT.</td></tr><tr><td>Proximal intercostal block</td><td>2024</td><td>Batnyam et al</td><td>Case series</td><td>15</td><td>47 % ICM; 47 % NICM; 6 % mixed</td><td>73.3 % MVT, 20 % PMVT; 20 % VF</td><td>162 ± 157 jours</td><td>After PICB, overall, the response rate to suppress VA was 75 %</td></tr><tr><td>Modified Sympathicotomy</td><td>2023</td><td>Cauti et al</td><td>Retrospective</td><td>15</td><td>26.7 % ICM; 73.3 % NICM</td><td>Not reported</td><td>Median 15 months (8.5 - 24.5 months)</td><td>Recurrence of sustained ventricular arrhythmias in 47 % of cases after a median follow-up of 15 months. Significant 91 % reduction in ICD shocks post-intervention</td></tr><tr><td rowspan="2">Stellate Ganglion Phototherapy<br>Transcutaneous Magnetic Stimulation</td><td>2021</td><td>Nonoguchi et al</td><td>Prospective, monocenter</td><td>11</td><td>27 % ICM; 55 % NICM; 18 % other</td><td>64 % MVT, 18 % VF; 18 % mixed VT / VF</td><td>Not reported</td><td>In 7 of the patients, ES was suppressed by stellate ganglion phototherapy.</td></tr><tr><td>2022</td><td>Markman et al</td><td>Double-blind, sham-controlled randomized clinical trial</td><td>26</td><td>50 % ICM, 42 % NICM, 8 % other</td><td>61 % VMT; 39 % PMVF</td><td>72 hours</td><td>Although 24-hour freedom from VT was not different between groups, there was a substantial reduction in the number of episodes of VT in the 72-hour period</td></tr></tbody></table>

ES = Electrical storm; ICD = Implantable cardioverter defibrillator; ICM = Ischemic cardiomyopathy; MVT = Monomorphic ventricular tachycardia; NICM = Non ischemic cardiomyopathy; PMVT = Polymorphic ventricular tachycardia; PSGB = Percutaneous Stellate Ganglion Block; RSD = Renal sympathetic denervation; SSD = Surgical sympathetic denervation; VA = Ventricular arrhythmia; VT = Ventricular tachycardia; VF = ventricular fibrillation.
<table><caption>**Table 2**
Characteristics of Currently Available Sympathetic Modulation Techniques in Humans.</caption><thead><tr><th>Technique</th><th>Invasive</th><th>Actions</th><th>Advantage</th><th>Disadvantages</th></tr></thead><tbody><tr><td>Thoracic Epidural Anesthesia</td><td>Invasive</td><td>Sympathetic chain blockade from T1 to T4</td><td>Immediate and titratable action<br>Bridge to a definitive therapeutic alternative</td><td>No parameters for tracking effectiveness<br>Patients on anticoagulants or dual antiplatelet therapy are not eligible</td></tr><tr><td>Percutaneous Stellate Ganglion Block</td><td>Minimally invasive</td><td>Stellate ganglion blockade</td><td>Immediate and titratable action<br>Bridge to a definitive therapeutic alternative<br>Patients on anticoagulants therapy are eligible</td><td>Rare complications: hematoma, pneumothorax, and laryngeal nerve blocks</td></tr><tr><td>Surgical Sympathetic Denervation</td><td>Invasive</td><td>Remove the lower half of the stellate ganglion and thoracic ganglia from T2 to T4</td><td>Definitive denervation<br>Refractory ventricular storms without alternative therapeutic: salvage procedure</td><td>Contraindicated: chronic obstructive pulmonary disease, anticoagulants therapy<br>General anesthesia<br>Reduced effectiveness immediately after the procedure</td></tr><tr><td>Renal Sympathetic Denervation</td><td>Minimally invasive</td><td>Ablation lesions in the renal arteries by radiofrequency</td><td>Reduction in ventricular arrhythmia rates over the medium term</td><td>No permanent denervation<br>No general anesthesia<br>Procedure success fluctuates depending on the anatomy of the renal arteries</td></tr><tr><td>Stellate ganglion ablation using radiofrequency</td><td>Minimally invasive</td><td>Stellate ganglion blockade</td><td>Reduction in ventricular arrhythmia rates over the mid-term</td><td>Partial denervation<br>No studies<br>No general anesthesia<br>Technical mastery</td></tr><tr><td>Proximal intercostal block</td><td>Minimally invasive</td><td>Target T1-T2: stellate ganglion and upper thoracic sympathetics blockage</td><td>Immediate and titratable action<br>Interesting alternative block (particularly in patients with challenging anatomy)</td><td>No studies<br>No general anesthesia<br>Technical mastery</td></tr><tr><td>Modified Sympathicotomy</td><td>Invasive</td><td>Radiofrequency sympatheticotomy from T2 to T5 and accessory fibers</td><td>Reduction in operative time<br>Fewer procedural complications than SSD<br>Avoid Horner's syndrome</td><td>Do not provide definitive denervation (sparing the synapses of stellate ganglion)<br>General anesthesia</td></tr><tr><td>Stellate Ganglion Phototherapy</td><td>Noninvasive</td><td>Target stellate ganglion</td><td>Non-invasive alternative<br>No procedural complications<br>Can be repeated and adjusted easily</td><td>Further studies are needed<br>Requires specialized equipment</td></tr><tr><td>Transcutaneous Magnetic Stimulation</td><td>Noninvasive</td><td>Target stellate ganglion</td><td>Non-invasive alternative<br>No procedural complications</td><td>Further studies are needed</td></tr></tbody></table>

Historically described in 1934 [29], this procedure was frequently performed for painful syndromes and showed efficacy through increased skin temperature on the ipsilateral back of the hand and pain reduction. The antiarrhythmic effects of left PSGB were first studied in animal models, where post-myocardial infarction rabbits and canines demonstrated decreased repolarization heterogeneity, prolonged ventricular refractory periods, and elevated ventricular fibrillation thresholds [30–32]. The first human case reported in 1976 by Grossman involved a patient with acute subarachnoid hemorrhage complicated by multiple VA [33]. Subsequent case reports [33–36] or case series [37], primarily from the early 2010s, have highlighted the growing interest in the PSGB technique as part of autonomic modulation for arrhythmia management. In 2017, two meta-analyses involving 35 and 38 patients, respectively, demonstrated a significant reduction in VA within 24 hours post-procedure, regardless of underlying cardiac pathology, type of VA, or left ventricular function [38,39]. These results have

been supported by numerous studies, both single-center [40–43] and multicenter [44,45], showing the consistent efficacy and safety of PSGB, whether unilateral or bilateral. Techniques varied across studies, particularly in terms of the choice of approach (anterior vs. lateral), type of anesthetic used, and method of administration (bolus alone vs. bolus with continuous infusion).

In 2024, the STAR study [46], a prospective multicenter trial involving 117 patients, further validated these findings. The study reported that 92 % of patients experienced at least a 50 % reduction in arrhythmic events within 12 hours post-PSGB compared to 12 hours before the procedure, with only one major complication (systemic local anesthetic toxicity). Interestingly, the study found no significant difference in antiarrhythmic efficacy based on the presence of anisocoria or volume of procedures performed at the center. However, an anterior anatomical approach was shown to be more effective than a lateral ultrasound-guided approach, although this finding may have been confounded by the higher baseline ar-
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Schematic representation of thoracic epidural anesthesia: inserting the catheter into the epidural space. Adapted with permission from Do et al. [26].</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Schematic representation of the two approaches for stellate ganglion block. The anatomical anterior paratracheal approach is depicted on the left, with the hand position and puncture site illustrated in the upper section. The ultrasound-guided lateral approach is shown on the right, with ultrasound landmarks displayed in the upper section, where the yellow star indicates the target zone. Adapted with permission from Savastano et al. [46].</figcaption></figure>

rhythmic burden in the anatomical group. In addition to the efficacy and safety, the timing of the procedure has emerged as a critical factor. Jiravsky et al. [47] developed a two-step algorithm emphasizing early PSGB. In their study of 59 patients with electrical storm, initial management included addressing predisposing factors, administering antiarrhythmic drugs (beta-blockers, amiodarone), mild sedation, and implantable cardioverter defibrillator reprogramming. LSGB was performed only if these measures failed while awaiting definitive therapies such as ablation, cardiac transplantation, or mechanical support. The mean time from electrical storm onset to PSGB was 13.2 ± 12.3 hours. Their results showed a reduction in shock and antitachycardia pacing (ATP) by 87 % and 65.9 %, respectively, within 48 h, with the most pronounced effects observed in patients with the highest arrhythmic burden. The in-hospital mortality rate was 8.8 %. These findings support the early implementation of PSGB for managing VA storms, particularly in stabilizing patients.

In conclusion, similar to TEA, PSBG can serve as a bridge to a definitive therapeutic alternative, acutely stabilizing patients.

### Surgical sympathetic denervation – Fig. 4

SSD was first used in the treatment of angina in 1921 [48], and later for arrhythmias in 1961 [49], initially involving an open thoracic approach. In 1980, Schwartz and Stone [50] demonstrated that left stellctomy exerts a major protective effect in reducing VF during episodes of myocardial ischemia in dogs with a previous myocardial infarction.

Currently, endoscopic methods are most commonly used. This technique is performed under general anesthesia through videothoracoscopy, with three approximately 1.5 to 2 cm subaxillary incisions associated with ipsilateral lung deflation. The objective is to remove the lower half of the stellate ganglion and thoracic ganglia from T2 to T4, located behind the parietal pleura.
<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Surgical sympathetic denervation: removal of the lower half of the stellate ganglion and the T2-T4 thoracic chain via video-assisted thoracoscopic surgery. Adapted with permission from Collura et al. [54].</figcaption></figure>

Sympathetic fibers directed towards the ocular region are usually spared, as they are mostly in the upper part of the stellate ganglion. This technique allows preganglionic denervation and synapse removal, which do not regenerate. The denervation effect is often better in the chronic phase than immediately after intervention (due to massive neuraxial activation, and it takes several weeks for distal neurotransmitter stores to empty out after SSD, which may increase vulnerability for sympathetic-driven ventricular arrhythmogenesis in the early period) [51]. No reinnervation has been observed over time because the postganglionic neurons that reside in the sympathetic chain are removed. This technique presents non-negligible risks, notably requiring general anesthesia. Patients with severe chronic obstructive pulmonary disease, therapeutic anticoagulation, or shock state are contraindicated to this procedure. Shah et al. reported complications in 49 out of 173 patients, representing 28 % of the study population: transient hypotension (9 %), pneumothorax (5 %), neuropathic pain (4 %), Horner syndrome (3 %), sweating pattern changes (3 %), and hemothorax (2 %) were

the most common complications [52]. Despite high perioperative risk, most patients do not experience severe complications.

In the early 2000s, studies on sympathetic denervation were primarily conducted in patients with long QT syndrome (note that immediately after SSD, a shortened QT interval is observed) and catecholaminergic polymorphic ventricular tachycardia exhibiting refractory VA. Left or bilateral SSD was performed with satisfactory long-term results (significant reduction in the number of implantable cardioverter defibrillator shocks over several years) [53–55]. Subsequently, several case reports [56–59,69] and retrospective series [60–68,70–72] have been published in the context of structural heart disease, demonstrating variable but relatively encouraging efficacy. The largest retrospective series [64], involving 121 patients with refractory VT undergoing left or bilateral SSD, was published in 2017 and reported an 88 % reduction in implantable cardioverter defibrillator shocks and a 50 % survival rate free from implantable cardioverter defibrillator shocks at 1 year. A procedure limited to the left side was an independent predictor of poorer implantable cardioverter defibrillator shock-free survival than bilateral SSD in this population. These findings were further corroborated by a meta-analysis conducted in 2020 [73] that included 311 patients. This analysis highlighted a pooled VT nonrecurrence rate of 60 % after SSD across all causes of arrhythmia, with a rate of 50 % specifically in structural heart disease after 15 ± 10.7 months. No procedure-related mortality was reported in this study. One year later, Chihara et al. [74] conducted a systematic review of 275 patients who underwent SSD for refractory VT and reported similar findings. The pooled nonrecurrence rate of VA was 62.2 %. Furthermore, 52.4 % of the patients were alive and free from implantable cardioverter defibrillator shocks or heart transplantation after an average follow-up of 1.38 years following left or bilateral denervation. The outcomes were less favorable when the procedure was performed in the context of an electrical storm. Only one death directly attributable to SSD has been reported. Interestingly, statistically higher mortality and transplantation rates were associated with patients undergoing the left thoracoscopic approach. The question of whether bilateral surgery is superior remains open, as studies on canine models comparing left, right, and

<figure><img src="image_8.png" /><figcaption>**Fig. 5.** A: A conceptual diagram illustrating the renal artery and its surrounding structures. It highlights the size mismatch between the ablation catheter and the renal artery, as well as the nonspecific ablation lesions that target only a subset of the renal nerves. B: A renal angiogram depicting the right renal artery. C: A standard 3.5-mm irrigated tip ablation catheter positioned at the bifurcation of the renal artery, based on the angiogram shown in panel B. Adapted with permission from Bradfield et al. [80].</figcaption></figure>
bilateral sympathectomy have demonstrated the most pronounced antiarrhythmic effects with bilateral sympathectomy[75], indicat- ing potentially greater efficacy. However, left-sided surgery may be favored due to its shorter operative time.

In conclusion, in cases of refractory VA storm with no alterna- tive therapeutic options, SSD can be considered as a salvage proce- dure when performed by experienced operators.

Renal sympathetic denervation – Fig. 5

This technique, historically used in resistant hypertension [76], has proven effective in reducing atrial fibrillation inducibility and sympathetic activity in recurrent VA. The first demonstration in humans occurred in 2011 [77]. In severe heart disease, im- paired cardiac output frequently activates the renin-angiotensin- aldosterone system, leading to myocardial fibrosis, ion distur- bances, and norepinephrine release. norepinephrine acts on an- giotensin II sympathetic receptors and contributes to the onset of VA. RSD can reduce norepinephrine levels in the body by 42 % and efferent sympathetic activity by 66 % [78]. In animal studies, par- ticularly in myocardial infarction models, RSD has been shown to reduce VF during ischemia, decrease neuropeptide Y levels, and re- model cardiac neurons and stellate ganglia [79].

RSD is performed percutaneously via the femoral artery, with renal angiography conducted at the beginning and end of the pro- cedure to confirm arterial patency. Typically, 4–6 ablation lesions are created in the renal arteries, from the distal to the proximal renal artery ostium, by using a spiral catheter for circumferential radiofrequency ablation [80]. This eliminates both the afferent and efferent renal sympathetic nerves. Anatomical variability, which cannot be evaluated using specific parameters, may affect proce- dural success. Sympathetic denervation is not permanent, reinner- vation has been observed in animal models after a few months.⁸¹ RSD appears relatively safe and well-tolerated. In patients with resistant hypertension, the most common long-term outcome is postprocedural blood pressure reduction, which often necessitates medication adjustments. Interestingly, post-RSD hypotension re- quiring medication reduction was not observed in trials involving patients with heart failure who typically had lower baseline blood pressure. This could be attributed to the differential effects of RSD in sympathetically driven hypertension.⁸²

Since its introduction, several case reports and case series, both retrospective and prospective, single-center and multicenter, have been published on the use of RSD in treating VT or electric storm in patients with ischemic and non-ischemic cardiomyopathy series⁸³⁻⁸⁹. According to these reports, RSD effectively reduced VT episodes and was deemed safe, with no notable decrease in blood pressure or deterioration in renal function. Two reviews⁹⁰,⁹¹ pub- lished in 2021, including 121 and 51 patients, respectively, con- firmed a significant reduction in the number of VA episodes and implantable cardioverter defibrillator therapies over follow-up pe- riods of several months. Further studies are required to better de- fine the role of this technique in the management of ESs.

New approaches - table 1 and 2

Recently, new techniques have emerged to address the limita- tions of historical methods.

Stellate ganglion ablation using radiofrequency ablation or
cryoablation

To avoid surgical intervention while achieving a more durable sympathetic blockade, Hygriv Rao et al⁹² had developed stellate ganglion ablation using conventional radiofrequency. An anterior tracheal approach under fluoroscopic guidance is used to target

C7. Using a radiofrequency generator, three lesions are created at 50, 55, and 60 °C for 90 s each. Then, the T1 vertebra is identi- fied, and the needle is placed at the junction of the vertebral body and the corresponding transverse process, allowing the creation of three new lesions by radiofrequency at 70 °C for 60 s each. This procedure is replicated on the right side. In this study, six patients with refractory electrical storms were included. This approach was successful in stopping electrical storm in all patients. After an av- erage follow-up of 22 ± 8 months, two patients received appro- priate shocks for VT. The Horner syndrome observed at the end of the intervention was transient in all cases. Unlike bilateral SSD, this procedure can be performed without general anesthesia and has a low rate of complications, including no risk of pneumoth- orax. However, it should be noted that this technique may only result in partial denervation. Similarly, another study employed a cryoablation technique under ultrasound guidance at the C6 level in a patient experiencing refractory electrical storm, resulting in an absence of VA events for 5 months.⁹³

Proximal intercostal block

The proximal intercostal block, first described by Bains et al.⁹⁴, is based on the injection of a local anesthetic into the space be- tween the internal intercostal membrane and endothoracic fascia and parietal pleura. This region is directly connected to the adja- cent paravertebral space, which contains the spinal nerves, rami communicants, and the sympathetic chain. As the stellate ganglion is formed by the fusion of the lower cervical sympathetic ganglia and the first thoracic sympathetic ganglia, a proximal intercostal block injection at the T1-T2 level can target this ganglion, similar to a traditional PGSB. In addition, proximal intercostal block offers the potential advantage of blocking the upper thoracic sympathetic ganglia. This procedure, which can be performed with the patient in either the seated or lateral position, involves administration of a bolus of local anesthetic at the T1-T2 level under high-resolution ultrasound guidance, followed by catheter placement for contin- uous infusion. In a recent series⁹⁵, this technique demonstrated reliable and effective sympathetic blockade, resulting in interrup- tion of VA in 77 % (11/15) of patients with refractory ventricu- lar storms. Thus, proximal intercostal block could be considered as a promising alternative, particularly for patients with challenging anatomies.

Modified sympatheticotomy

First performed in 202,¹⁹⁶, modified sympatheticotomy is per- formed under general anesthesia with the patient positioned in the decubitus position, semi-sitting, and arms spread to optimize ac- cess to the axillary region. A single incision is made in the second intercostal space at the axilla, allowing the insertion of a 5 mm camera to visualize the sympathetic chain. Using the same inci- sion, an electrified hook set to 80 W is introduced to perform ra- diofrequency sympatheticotomy from T2 to T5, targeting accessory fibers (notably the nerve of Kuntz), while preserving the stellate ganglion. A recent study⁹⁷, published in 2023, involving 15 pa- tients, reported a recurrence of sustained VA in 47 % of cases af- ter a median follow-up of 15 months. Despite this, there was a significant 91 % reduction in implantable cardioverter defibrillator shocks post-intervention (3.1 shocks per patient pre-intervention vs. 0.3 shocks per patient post-intervention; *p* = 0.001). No ma- jor periprocedural complications were noted. Compared to classi- cal SSD, this method offers several advantages, including reduced operative time, fewer procedural complications, and avoidance of Horner's syndrome, thereby making the technique more accessible to a wider range of patients. However, it is important to note that this approach may not achieve definitive denervation as it spares
the synapses of the stellate ganglia. This preservation increases the potential for reinnervation over time owing to nerve sprouting.

## Stellate ganglion phototherapy

Stellate ganglion phototherapy is a noninvasive alternative to PGSB, initially developed for the management of neuropathic pain⁹⁸ and later applied to VA. The first documented case was reported in 2020 by Sato et al.⁹⁹ in a patient with non-ischemic cardiomyopathy awaiting cardiac transplantation and experiencing recurrent ventricular tachycardias. Stellate ganglion phototherapy was performed in a seated position using a semiconductor laser, with the probe placed near the stellate ganglion and irradiated daily for 5 min on each side. After one month of follow-up, no VT recurrence was observed. In 2021, Nomoguchi et al. conducted¹⁰⁰ a prospective monocentric study of 11 patients with refractory electrical storms. Stellate ganglion phototherapy reduced the burden of VA from 8.0 ± 9.0 episodes per day to an average of 2.0 ± 5.3 episodes per day. Seven patients achieved complete suppression of the VA episodes. However, the effects of stellate ganglion phototherapy appear to be temporary. Among the seven patients with complete suppression, two out of three receiving maintenance therapy by stellate ganglion phototherapy experienced VT recurrence, while among the four patients without maintenance therapy, two also experienced recurrences. No adverse events were observed. The duration of phototherapy effectiveness varies from several hours to several weeks¹⁰¹,¹⁰². Consequently, stellate ganglion phototherapy may serve as a temporary treatment to stabilize patients with electrical storms prior to catheter ablation or other interventions. It may also help to reduce the recurrence of rhythmic episodes with chronic use, although further studies are needed to confirm these benefits.

## Transcutaneous magnetic stimulation

This method, known for its applications in pain centers and drug-resistant depression¹⁰³, has demonstrated potential effect in animal models to reduce the risk of VA¹⁰⁴. Transcutaneous magnetic stimulation is a noninvasive and nondestructive method for modulating autonomic nervous system activity. It involves repetitive transcranial magnetic stimulation that emits a series of magnetic pulses during a given time interval to modify the activity of the targeted region. It was first reported for the treatment of refractory electrical storm in five patients by targeting the left stellate ganglion¹⁰⁵. This resulted in a reduction in VT rates with no reported adverse effects. A phase 3 randomized¹⁰⁶, double-blind, monocentric study was later published in 2023, analyzing the effect of a single session of transcutaneous magnetic stimulation in patients with electrical storm. Twenty-six patients with refractory electrical storm despite multiple antiarrhythmics were included. The primary outcome was the absence of sustained VT within 24 hours following stimulation. In the 24-hour period after randomization, VT recurred in 4 of 14 patients (29 %) in the stimulation group vs. 7 of 12 patients (58 %) in the sham group (P = 0.20). In the 72-hour period after randomization, patients in the stimulation group had a mean of 4.5 (7.2) episodes of VT vs. 10.7 (13.8) in the sham group (incidence rate ratio, 0.42; P < 0.001). No interference with the implantable cardioverter defibrillator was observed; none of the device parameters — including sensing, pacing thresholds, or lead impedances — showed any clinically significant changes. Only four patients exhibited signs of peripheral block, and these patients did not have VT recurrence within 24 h. The study's limitations included a small sample size and a likely need for optimization of the stimulation protocol (patients were stimulated at 80 % of the motor threshold at 0.9 Hz for 60 min). In conclusion,

transcutaneous magnetic stimulation could be a noninvasive alternative with the potential to safely reduce the burden of VA during electrical storms.

## Future approaches

### Pharmacological approaches

Currently, various treatments are available to modulate sympathetic activity. Beta-blockers, which have been used since the 1950s, can be either cardio-selective or nonselective. However, even at maximum doses, these treatments often fail to eliminate VA in certain situations. neuropeptide Y is a neurotransmitter that inhibits the parasympathetic system, causing a decrease in presynaptic acetylcholine release through action on the neuropeptide Y Y2 receptor¹⁰⁷. Additionally, it induces an increase in transient calcium levels (Ca2+ sparks) after the activation of the neuropeptide Y Y1 receptor, which stimulates phospholipase C¹⁰⁸. Neuropeptide Y levels are elevated in patients with severe heart failure¹⁰⁹, and a high neuropeptide Y level in individuals who have recently experienced a heart attack is associated with an increased risk of heart failure, ventricular dysfunction, and arrhythmias.¹¹⁰,¹¹¹

To counteract the effects of neuropeptide Y, a drug named BIBO3304 has been developed. BIBO3304 is a potent, orally active, selective neuropeptide Y Y1 receptor antagonist. In an experimental protocol conducted in pigs, this treatment has shown the ability to reduce the shortening of the post-activation recovery interval by approximately 10 ms. It also increases the VF threshold, coupled with simultaneous improvement in inotropy. These effects are crucial for managing ventricular storms, especially in patients with advanced heart disease and severely reduced left ventricular ejection fraction. The development of pharmacological agents targeting neuropeptide Y receptors presents a promising avenue for future therapeutic interventions in VAs [10]. Studies in humans are pending.

### Carotid baroreceptor stimulation

Baroreceptors are located in the carotid sinus at the initial part of the internal carotid artery. The activation of afferent fibers originating from the glossopharyngeal nerves in the thickened wall of the baroreceptors stimulates efferent fibers, inhibits sympathetic activity, and activates the parasympathetic system. A 2014 study in dogs demonstrated that electrically stimulating carotid baroreceptors led to an increase in the ventricular refractory period and a decrease in the number of VT/VF episodes.¹¹² This was further confirmed by another series comparing VA episodes in dogs after myocardial infarction induction between the low-level baroreceptor stimulation group and the control group (7 ± 3 in the control group versus 3 ± 2 in the carotid baroreceptor stimulation group, P < 0.05).¹¹³ This technique has not yet been tested to reduce VA in humans.

### Aorto-renal ganglion ablation

The aorto-renal ganglia are interconnected with the celiac and superior mesenteric ganglia via nerve fibers. These ganglia are exclusively sympathetic and contain cholinergic and sensory afferent fibers. In 2019, high-frequency stimulation of these ganglia, located near the inferior vena cava and the aorta, was performed in sheep to evaluate the effectiveness of renal artery denervation, with the abolition of vasoconstriction during aorto-renal ganglion stimulation¹¹⁴. In 2021, Hori et al. investigated the impact of ablat-ing ganglia in pigs and demonstrated a protective effect against VA and sudden death. Furthermore, the study revealed that ganglion ablation eliminated systolic blood pressure variation responses not
only at the level of the ganglia but also in the renal artery when renal artery stimulation and aorto-renal ganglion stimulation were performed. This effect was not observed in renal artery ablation alone¹¹⁵. To date, no study has been conducted in humans.

### Axonal modulation therapy

Axonal neuromodulation was shown in 2015 to selectively block action potential propagation using either kilohertz-frequency alternating current or direct current¹¹⁶. Mechanisms include sustained potassium channel activation or sodium channel inactivation, with blocking frequencies ranging from 200 Hz to 30 kHz¹¹⁷. In 2017, balanced direct current stimulation of the T1–T2 paravertebral chain in infarcted pigs reduced ventricular arrhythmias and prolonged the refractory period without impairing cardiac function¹¹⁸. These findings were confirmed in 2022 using alternating current stimulation at T1–T3, which also decreased circulating norepinephrine. This strategy may support on-demand neuromodulation alongside conventional therapies.¹¹⁹

### Glial cell modulation

Glial cells in the sympathetic ganglia can interact through direct activation, as they express neurotransmitter receptors, potassium channels, and neurotransmitter transporters. Initial studies have shown that activation of the Gq-coupled receptor protein in glial cells expressing glial fibrillary acidic protein plays a role in the homeostatic control of blood gases and intestinal mobility. Recent studies focusing on cardiac function have revealed the impact of these peripheral glial cells on the sympathetic ganglion due to Gq-coupled receptor protein activation (via a synthetic drug DRE-ADD), regulating blood pressure and heart rate. An increase in norepinephrine release and activation of beta-1 adrenergic receptors was also observed.¹²⁰ Therefore, suppression of Gq-coupled receptor protein signaling in sympathetic glial cells has the potential to reduce sympathetic overactivation.

### Desensitization using resoriniferatoxin

The cardiac sympathetic afferent reflex is partially mediated by the activation of channels, such as TRPV1, a capsaicin-activated channel. Studies have demonstrated that epicardial application of capsaicin (or bradykinin) elicits responses similar to those observed during myocardial infarction. Desensitization using resoriniferatoxin, a potent capsaicin analog first used in 1989,¹²¹, is responsible for the degeneration of afferent neurons. Histological evidence confirmed the presence of TRPV1-expressing afferent nerves in the heart. Additionally, the sympathetic reflex response induced by epicardial bradykinin was inhibited in rats treated with desensitization using resoriniferatoxin, emphasizing the importance of capsaicin-sensitive afferent nerves in the sympathetic-excitatory myocardial reflex. However, the bradykinin-triggered reflex response is not dependent on TRPV1 receptors, as evidenced by the lack of inhibition with iodo-desensitization using resoriniferatoxin (a TRPV1 antagonist) but depends on cardiac afferent fibers expressing TRPV1.¹²² This reveals potential targets through these afferent fibers to reduce VA.

### Interleukin neuroimmunotherapy

Interleukins are cytokines produced by various immune system cells that act as messengers to facilitate communication between different immune system components. A 2023 study using adeno-associated viral vectors to overexpress IL-6 in the left stellate ganglion of infarcted beagles demonstrated enhanced sympathetic activity and increased susceptibility to ventricular arrhythmias.¹²³ In contrast, targeted overexpression of IL-10 in a similar model led to reduced sympathetic nerve activity, fewer tyrosine hydroxylase-positive neurons, decreased norepinephrine levels, and lower inflammatory markers, resulting in fewer arrhythmic events.¹²⁴ These findings suggest that targeted cytokine modulation at the neural level may help prevent or attenuate postinfarction ventricular arrhythmias.

### Local hyperthermia therapy

The creation of local hyperthermia through aggregation-induced emission luminogen-based covalent organic frameworks has been shown to limit the occurrence of VA.¹²⁵ These materials have two main actions: modulation of stellate ganglion neuronal activity through local hyperthermia therapy, and improvement of the surrounding neuroinflammation. Further studies are warranted to better understand the mechanisms and implications of such strategy.

### Vagal nerve stimulation

Preclinical studies have highlighted the potential of vagal nerve stimulation in the prevention of post-infarction ventricular arrhythmias. As early as 1991, Vanoli et al. demonstrated that stimulation of the tragus nerve, by enhancing parasympathetic activity, significantly reduced the incidence of ventricular arrhythmias in conscious dogs with healed myocardial infarction.¹²⁶ These findings were more recently confirmed by Nasi-Er et al., who showed that transcutaneous stimulation of the auricular branch of the vagus nerve reduced the occurrence of spontaneous ventricular arrhythmias in post-infarction dogs and improved ventricular electrical stability.¹²⁷

### Current recommendations

Presently, the European Society of Cardiology [1] classifies sympathetic modulation as class IIb-C for patients with refractory electrical storms unresponsive to medical treatment and when catheter ablation is not effective or feasible. Notably, left surgical sympathetic denervation is indicated as class I-C for patients with symptomatic congenital long QT syndrome under beta-blocker therapy with refractory VA. This approach has also shown some interest in catecholaminergic ventricular tachycardia (class IIa).¹²⁸

To date, no standardized therapeutic sequence exists for neuromodulation in electrical storm. The duration of effect varies by technique: some offer short-term relief (PSGB, TEA), others provide intermediate effects (RSD), while some aim for long-term sympathetic suppression (SSD). The approach is typically guided by a multidisciplinary evaluation tailored to the patient's clinical profile.

### Conclusion

Overall, sympathetic modulation is a promising and generally safe approach for managing refractory electrical storm. Various invasive and non-invasive techniques offer options for either permanent or temporary sympathetic denervation. Emerging strategies are currently under investigation, and while robust evidence is still limited, the indications for targeted sympathetic modulation are expected to broaden in the near future.

### Declaration of competing interest

None.
CRediT authorship contribution statement

**Pierre Groussin:** Writing – review & editing, Writing – original draft, Conceptualization. **Donovan Decaudin:** Supervision. **Melvyn Dezecot:** Visualization. **Thomas Marc:** Supervision. **Nathalie Behar:** Validation. **Dominique Pavin:** Supervision. **Christophe Leclercq:** Validation. **Philippe Mabo:** Validation, Supervision. **Karim Benali:** Validation. **RaphaëlP. Martins:** Visualization, Validation, Supervision.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.tcm.2025.05.001.

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