Review Article

Cardiac Sympathetic Innervation and Ventricular Arrhythmias in Structural Heart Disease: Current Peripheral Neuromodulation Therapies and Emerging Therapeutic Targets

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Abstract

Over the past several decades, substantial evidence has pointed to the role of the autonomic nervous system in the genesis and maintenance of ventricular arrhythmia. In particular, sympathetic activation has been shown to increase the risk of ventricular arrhythmia, particularly in the context of structural heart diseases, and is a key target of neuromodulatory therapies. Current peripheral sympathetic neuromodulatory approaches include temporary interventions, such as stellate ganglion block, proximal intercostal block, and thoracic epidural anaesthesia, as well as more definitive therapies, such as cardiac sympathetic denervation and renal denervation. Each of these approaches presents distinct strengths and limitations, as well as side effects that warrant careful consideration in clinical practice and highlight the need for more targeted strategies. Emerging interventions focusing on neuropeptide Y, sympathetic afferents ablation, high-frequency block of efferent nerves, and the restoration of sympathetic innervation after MI have shown promising potential. However, further research is needed to evaluate the feasibility and safety of these novel therapies prior to their implementation in patients with cardiovascular diseases.

Keywords

Autonomic nervous system, sympathetic, neuromodulation, ventricular arrhythmia, neuropeptide Y, TRPV1,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/aer.2025.24

Disclosure: MV has received honoraria from Zoll and Abbott, has shares in NeuCures and Anumana and is vice chair of the Heart Rhythm Society Research Committee. LB has no conflicts of interest to declare.

Funding: This study was supported by grants from the National Institutes of Health (NIHR01HL148190 and NIHR01HL170626) to MV.

Correspondence: Marmar Vaseghi, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, US. E: mvaseghi@mednet.ucla.edu

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The cardiac autonomic nervous system (ANS) profoundly influences cardiac electrophysiology and is integral to the mechanisms underlying arrhythmogenesis in cardiovascular disease.1,2 Structural heart diseases, such as MI and heart failure, are characterised by increased sympathetic activity and reduced parasympathetic tone, changes that promote disease progression and increase susceptibility to arrhythmias.3–6 This review examines the role of the sympathetic nervous system in the genesis of ventricular arrhythmias (VAs), evaluates existing peripheral sympathetic neuromodulatory therapies and their strengths and limitations, and highlights emerging targets for sympathetic modulation.

Role of Autonomic Nervous System Remodelling in the Pathogenesis of Scar-mediated Ventricular Arrhythmias

Myocardial injury is accompanied by increased cardiac sympathetic tone and a parallel reduction in parasympathetic tone.6 Although these autonomic changes initially serve as compensatory mechanisms to maintain cardiac output, prolonged sympathetic dominance has deleterious cardiovascular effects and is pro-arrhythmic.6,7 Accordingly, elevated plasma concentrations of noradrenaline (NA) and neuropeptide Y (NPY) in patients with cardiovascular disease are associated with increased risk of VAs and mortality.8–11

The observed autonomic imbalance in structural heart disease (SHD) is accompanied by functional and morphological remodelling at various levels of the cardiac neuraxis. In both the right and left stellate ganglia (SG), postganglionic sympathetic neurons exhibit increased synaptic density and structural changes, including neurochemical remodelling.12,13 In addition, several preclinical electrophysiological studies have demonstrated increased activity of SG neurons after MI.12,14

Notably, structural and functional changes also occur in the nodose/vagal ganglia after MI, resulting in what appears to be alterations in vagal afferent neurotransmission. These alterations ultimately result in reduced cardiac vagal tone, although the underlying mechanisms require further investigation.15–17

Cardiac injury and disease also lead to significant neuronal remodelling within the heart, disrupting the distribution and density of cardiac nerves. MI results in denervation followed by localised hyperinnervation of border zone regions. Damage to sympathetic axons, which can occur concurrently with myocardial injury, promotes localised nerve sprouting in the infarct border zones, exacerbating heterogeneity in both myocardial conduction and repolarisation during sympathetic activation.18,19 Following MI, denervation occurs not only within the dense scar tissue but also in viable myocardial regions both adjacent to and remote from the scar.20,21 The denervated regions exhibit sympathetic denervation supersensitivity, characterised by an exaggerated response to catecholamines.22 With sympathetic activation, this phenomenon leads to a pronounced shortening of action potential duration in specific regions, while adjacent areas remain less responsive, resulting in enhanced dispersion of repolarisation and action potential duration.23 In patients with SHD, increased sympathetic nerve sprouting at the border zones of myocardial scars correlates with a heightened risk of VA.24 Furthermore, the extent of sympathetic denervation following MI serves as a predictor of VA and sudden cardiac arrest.25,26 Therefore, heterogeneity in innervation leading to electrophysiological dispersion appears to play a key role in predisposing to VAs. In this regard, periodic repolarisation dynamics, a marker of ventricular repolarisation instability, has been shown to correlate with efferent sympathetic nerve activity. Periodic repolarisation dynamics is independent of heart rate variability, and is mitigated by β-adrenergic receptor blockade and may, thereby, constitute a strong and independent predictor of mortality in patients after MI.27

Mechanical and chemical changes in the setting of myocardial injury are sensed by spinal afferent neurons, which, via peripheral and central reflexes, act to increase cardiac sympathetic efferent tone. In the setting of cardiovascular pathology, including MI, heart failure with reduced ejection fraction and hypertension, enhanced cardiac sympathetic afferent reflexes (CSAR) have been shown to contribute to the increased sympathetic outflow to the heart.28 These changes are also associated with structural remodelling within the dorsal root ganglia and spinal horns, with an increase in both the quantity and size of nociceptive afferent neurons following MI.29

Moreover, accumulating evidence indicates that in SHD, such as MI and heart failure, cardiac sympathetic neurons undergo a phenotypic switch (cholinergic transdifferentiation), likely mediated by inflammation-induced cytokine signalling, which results in the release of acetylcholine.30,31 Functional analyses using MI mouse models and optical mapping have suggested that this neurochemical remodelling may prolong action potential duration in both border zone and remote myocardial regions, while simultaneously reducing action potential duration heterogeneity.32

Current Peripheral Sympathetic Neuromodulation Therapies for Ventricular Arrhythmias: Advances and Limitations

The multitude of pathological changes in the peripheral sympathetic nervous system observed in the setting of SHD, combined with the strong link between elevated sympathetic tone and the risk of VAs, have provided the rationale for the development of neuromodulatory therapies targeting this system. Figure 1 highlights the key sympathetic neuromodulatory therapies currently in use, as well as emerging novel targets for therapeutic intervention. It is important to note that many of the guideline-directed therapies for the treatment of heart failure, including β-adrenergic receptor blockers and agents targeting the renin–angiotensin–aldosterone system, exert their effects by modulating the sympathetic nervous system and have been shown to reduce both mortality and VAs.33–36 The following sections will discuss specific therapies, beyond these medications, for the treatment of recurrent or refractory VA and electrical storm.

Figure 1: Principal Current Sympathetic Neuromodulatory Therapies and Novel Potential Neuromodulatory Targets

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Stellate Ganglion Modulation

SG block is a frequently used neuromodulation therapy in the management of electrical storm.37 It is performed by percutaneous injection of local anaesthetic agents (predominantly bupivacaine and ropivacaine) at the level of the SG. The SG serve as a strategic nexus point for targeting cardiac adrenergic activation. Afferent fibres from the heart to the central nervous system pass through these ganglia, which also serve as the site of efferent preganglionic to postganglionic sympathetic neurotransmission. Moreover, unlike adrenergic receptor blockade, SG block has the potential to attenuate not only NA-mediated sympathetic activation, but also sympathetic activation mediated by sympathetic co-transmitters, such as NPY or galanin, offering more complete sympathetic blockade than β-blocker therapy. Although bilateral SG have been targeted in some studies, most have evaluated left SG blockade, given that prior studies had demonstrated greater arrhythmogenicity with left compared with right SG activation, including increased dispersion of repolarisation.38–40 The key advantage of percutaneous SG block is the feasibility of performing the procedure at the bedside under ultrasound guidance, making it especially valuable in the urgent management of haemodynamically unstable patients experiencing electrical storm.

Until recently, clinical evidence supporting the efficacy of percutaneous SG blockade was limited to isolated case reports and small case series.41–43 Although randomised clinical trials are still lacking, the multicentre STAR study, which included 133 patients with electrical storm across 19 different centres, provided additional evidence for the effectiveness and safety of this procedure.44 In that cohort, over 92% of patients met the primary outcome of a ≥50% reduction in arrhythmic episodes after SG block, with only one significant complication observed, despite a high degree of patient comorbidities (i.e. a mean [±SD] left ventricular ejection fraction [LVEF] of 25.0±12.3%, 67% of patients on dual antiplatelet or anticoagulant therapy). Remarkably, the reduction in VA burden following SG block appears to be consistent across different cardiomyopathies, types of VAs (monomorphic versus polymorphic) and degrees of ventricular dysfunction.43

The primary limitation of SG block is its temporary effect, with the duration of block dependent on the half-life of the anaesthetic agent used. Therefore, SG block often serves as a bridge for more definitive therapies, such as catheter ablation, cardiac sympathetic denervation or heart transplantation. To extend the duration of sympathetic blockade, continuous infusion via a percutaneously placed catheter was implemented in a few case series, and has been associated with a greater reduction in VA burden, with a similar safety profile compared to a single injection.45,46 The most recent and largest meta-analysis of 61 patients demonstrated complete VA suppression in 61% of patients, with a mean duration of infusion of 4 days, thereby overcoming the need for repeat procedures.47 Nevertheless, continuous infusion remains constrained by its use exclusively in hospitalised patients and limits patient mobility.

Interestingly, SG modulation has also been reported in small case series of patients using phototherapy, obviating the need for an invasive procedure.48–50 Serum adrenaline concentrations in healthy participants were reportedly reduced, and 7 of 11 patients with electrical storm following SG phototherapy had a reduction in VA burden. Transcutaneous magnetic stimulation is another non-invasive modality recently reported to modulate sympathetic activity. Although in a randomised controlled trial of 26 patients with ventricular tachycardia (VT) storm a single session of transcutaneous magnetic stimulation targeting the left SG did not demonstrate superiority over a sham procedure in preventing VT recurrence within 24 hours, it was associated with a significant reduction in VT burden after 72 hours.51 Evidence for other reported approaches to achieve more sustained SG modulation, including chemical ablation via percutaneous alcohol injection, cryoablation and radiofrequency ablation, is limited to case reports.52–55

Batnyam et al. recently introduced proximal intercostal blockade (PICB) as a novel technique to reduce cardiac sympathetic tone in patients with electrical storm.56 This method delivers the anaesthetic agent at the T1 or T2 level, specifically targeting the layer between the internal intercostal membrane and the endothoracic fascia/parietal pleura complex. This anatomical region communicates with the paravertebral space and the endothoracic fascial plane, likely allowing the anaesthetic agent to reach the SG and thoracic ganglia. In a single-centre retrospective study, continuous bilateral PICB provided safe and effective sympathetic blockade, with 77.8% of the nine patients presenting with electrical storm (including four patients with ischemic cardiomyopathy) experiencing VA suppression.57 An advantage of PICB is that the access site is usually free from vascular lines and haemodynamic support devices. Furthermore, PICB targets a more posterior anatomical location, which is further from the recurrent laryngeal and phrenic nerves, reducing the risk of adverse effects such as vocal cord or diaphragmatic paralysis reported with SG block. However, the procedure is still limited to experienced centres, given the risk of pneumothorax, and remains a temporising measure.

Thoracic Epidural Anaesthesia

Similar to SG block and PICB, thoracic epidural anaesthesia (TEA) involves the administration of a local anaesthetic into the epidural space. This technique provides rapid and reversible sympathetic blockade by inhibiting both spinal afferent and sympathetic efferent pathways. Specifically, TEA blocks the spinal roots from the C8 to T4 levels bilaterally, thereby inhibiting fibres that are proximal to both the left and right SG. Case reports and small case series suggest that TEA may be effective in acutely treating electrical storm and reducing the burden of refractory VAs in patients with SHD.58,59 A small study examining the use of TEA in the treatment of electrical storm in patients with VT refractory to medical therapy and catheter ablation demonstrated a >80% reduction in VT episodes.58 A more recent meta-analysis, which included 22 patients (82% of SHDs), reported complete antiarrhythmic response in 59% of patients.47 In this meta-analysis, none of the TEA patients were receiving full anticoagulation therapy, whereas 68% of the patients receiving continuous-infusion SG block cohort were on anticoagulants. This points to one of the more important limitations of TEA: it cannot be instituted without discontinuing antiplatelet agents or anticoagulants due to the risk of epidural haematoma.

The antiarrhythmic mechanisms of TEA have been studied in large animal models. In a chronic MI porcine model, TEA increased ventricular effective refractory period and myocardial action potential duration, decreased the slope of ventricular restitution, and mitigated action potential dispersion in border zone regions.60 Similar to SG blockade, the primary limitation of TEA is related to the pharmacokinetics of the anaesthetic agents used. Furthermore, as mentioned above, unlike SG blockade, TEA cannot be implemented in the presence of on-going anticoagulation or dual antiplatelet therapy, limiting its use in many patients with SHD. In addition, contraindications to epidural catheter placement, such as bacteraemia or increased intracranial pressure, remain a concern. Side effects, although rare, include Horner’s syndrome (ptosis, anhidrosis, and miosis).

Surgical Cardiac Sympathetic Denervation

Surgical cardiac sympathetic denervation (CSD) is aimed at permanently interrupting most of the cardiac sympathetic efferent and afferent pathways by resecting the lower half to one-third of the SG, along with the thoracic sympathetic ganglia from T2 to T4. CSD is typically performed using a minimally invasive video-assisted thoracoscopic surgical approach. Following initial positive outcomes in patients with long QT syndrome and catecholaminergic polymorphic VT, CSD has also shown significant benefits in patients with SHD, including improvements in polymorphic VT and VF, as well as scar-mediated monomorphic VT burden and defibrillator shocks.61,62 Preclinical data have demonstrated that bilateral CSD effectively mitigates repolarisation dispersion during sympathetic activation and significantly reduces VT inducibility.63 Several retrospective studies have consistently reported a reduction in VT burden and improved arrhythmia-free survival in patients with SHD who underwent CSD, with bilateral CSD demonstrating greater efficacy than left CSD alone in reducing ventricular arrhythmias.62 In a multicentre study involving 121 patients with SHD who underwent either left or bilateral CSD for refractory VA, most of whom had non-ischaemic cardiomyopathy, 58.2% were free from ICD shocks or sustained VT at 1 year, and an 88% reduction in ICD shocks in the year after versus prior to CSD was observed.62 In a different cohort of 20 patients, primarily with SHD, bilateral CSD was associated with a sustained reduction in arrhythmias, demonstrating a 54.5% VT-free survival at 4 years.64 Recent data have also suggested the potential benefit of CSD in reducing the burden of premature ventricular contractions (PVCs).65,66 Ahmed et al. reported a significant reduction in PVC burden following bilateral CSD (1.3% post-CSD versus 23.7% pre-CSD; p<0.001), along with notable improvements in LVEF (46.3% post-CSD versus 38.7% pre-CSD; p<0.001).66 Therefore, CSD can serve as a possible treatment for the management of refractory PVC-related conditions, such as PVC-induced cardiomyopathy or PVC-induced polymorphic VT/VF, especially when PVCs originate from locations not amenable to ablation or in the presence of multifocal PVCs.

Nevertheless, CSD has several limitations. It may not be effective in a subset of patients with longer VT cycle lengths or patients with New York Heart Association Class IV heart failure.62 CSD is also associated with side effects such as neuropathic pain and dysaesthesia and an altered sweating pattern in approximately 10–15% of patients.67,68 In addition, CSD requires single-lung inflation, which may be prohibitive in critically ill patients.69 In this regard, a modified technique involving radiofrequency ablation of the T2–T4 sympathetic ganglia with SG sparing and without the need for pleural dissection was reported by Cauti et al., offering the potential to shorten procedural and single-lung ventilation duration and decrease the risk of complications. Additional studies are needed to confirm similar efficacy of this procedure to CSD involving removal of the lower half of the SG.70

Renal Sympathetic Denervation

Renal sympathetic nerves regulate cardiovascular function by releasing renin and thereby activating the renin–angiotensin–aldosterone system, which leads to vasoconstriction, increased sodium reabsorption and volume retention. In addition, renal sensory afferent nerves transmit signals from chemo- and mechano-receptors to the central nervous system via the dorsal root ganglia, modulating sympathetic renal and cardiac outflow. Renal denervation (RDN) has been traditionally performed from within the renal arteries, with the goal of ablating sympathetic efferent and spinal afferent fibres that run along these vessels.71 Ablation of these fibres within the adventitial layer disrupts leads to the inhibition of the renin–angiotensin–aldosterone system and attenuation of renal sympathetic afferent signalling, ultimately reducing efferent sympathetic activity to the heart.72

Given the central role of neurohormonal activation and heightened sympathetic tone in the pathogenesis of VA, RDN has emerged as a potential therapeutic option for VA management. It is important to note that RDN has also been noted to reduce inflammation in the cardiac ganglia.73 Preclinical studies have suggested a beneficial effect of RDN in reducing VAs. In a post-MI canine model, RDN induced favourable electrophysiological remodelling of infarct border zones, and was associated with reduction in VA occurrence.74 Similarly, in a porcine model, ablation of the aorticorenal ganglion, a predominantly adrenergic structure innervating the kidneys and formed by the convergence of splanchnic nerves from the sympathetic chain, protected against VA during acute myocardial ischaemia.75 Clinical data have further supported the antiarrhythmic potential of RDN, with multiple case series showing its benefits for patients with refractory VA.76–78 A meta-analysis of 121 patients published in 2021 found RDN to be an effective treatment for refractory VA and electrical storm, significantly reducing ICD therapies and VA episodes.79 Notably, when used as adjunctive therapy alongside CSD, RDN appeared to further decrease the risk of recurrent VT and ICD therapies in a retrospective study of 10 patients.80

RDN was initially investigated as a treatment for resistant hypertension and showed promising early results.81,82 However, later studies produced mixed findings, raising concerns about the procedure’s efficacy.83–86 This variability may be attributed to differences in the type of ablation strategy used, inconsistencies in ablation endpoints, local anatomical variations of structures surrounding the renal arteries, such as lymph nodes and small blood vessels, which influence complete ablation of nerve fibres, as well as a lack of data regarding the appropriate duration and amount of ablation.87 Overcoming these challenges will be critical for the effective application of RDN in the treatment of VA.

Potential Novel Neuromodulatory Targets

Given the limitations of current neuromodulatory therapies targeting the sympathetic nervous system, the development of more targeted strategies is warranted. Recent evidence highlights several emerging targets.

Neuropeptide Y

NPY is a sympathetic co-transmitter released from cardiac sympathetic nerve terminals with sympathoexcitation.88 NA can further act on presynaptic sympathetic β-adrenergic receptors at the level of the heart to promote the release of NPY.89 NPY has multiple cardiac autonomic effects. It reduces acetylcholine release from cardiac parasympathetic nerve endings via activation of Y2 receptors on presynaptic terminals, whereas NPY activation of ventricular Y1 receptors induces calcium overload and shortening of action potential duration, thereby promoting arrhythmogenesis.90–92 In vitro, NPY has been linked to enhanced automaticity in human cardiomyocytes.93 Elevated venous NPY concentrations have been linked to an increased risk of VA in ST-elevation MI, even in patients receiving β-blocker therapy.10,94 Moreover, elevated plasma NPY levels are a prognostic indicator of adverse clinical outcomes. Emerging evidence supports the role of NPY as a relevant biomarker for risk stratification in the context of electrical storm.95 Elevated plasma NPY concentrations have also been associated with microvascular dysfunction, greater infarct size and reduced LVEF after reperfusion therapy in acute MI.96–98

Several novel approaches have targeted NPY receptors in vitro and in animal models, in an effort to mitigate ventricular arrhythmogenesis. In the study by Kalla et al., combined β- and α-adrenergic receptor blockade failed to prevent the effects of SG stimulation on calcium transients and VF threshold ex vivo, whereas selective Y1 receptor blockade (with BIBO 3304) was shown to work synergistically with β-adrenergic receptor blockade to reduce these effects in isolated hearts.10 Moreover, Hoang et al. demonstrated that high-dose β-blocker therapy alone was insufficient to counteract the electrophysiological effects of sympathoexcitation, whereas Y1 receptor blockade (along with β-adrenergic receptor blockade) further inhibited these effects on ventricular action potential duration in vivo in a porcine model.92 In addition, studies in a porcine model have revealed that Y2 receptor blockade partially mitigated the proarrhythmic electrophysiological consequences of bilateral SG stimulation by improving vagal tone.99 Y2 receptor blockade has been reported to enhance the effects of vagal nerve stimulation during sympathetic activation, suggesting a potential adjunctive role for Y2 receptor antagonism as a therapeutic strategy aimed at reducing VA occurrence in the setting of sympathoexcitation.100 Additional studies, including in diseased animal models and humans, are needed to develop and evaluate the role of NPY Y1 and Y2 receptor blockade in the treatment of VAs and their potential extracardiac side effects.

Sympathetic Nociceptive Afferent Blockade as a Target for Neuromodulation

As stated above, augmented CSAR is a key contributor to enhanced sympathetic tone in the setting of cardiovascular disease. This reflex seems to be largely mediated by the transient receptor potential vanilloid 1 (TRPV1) channels on nerve endings, which are activated by stimuli such as capsaicin, nociceptive compounds, heat and several metabolites generated during ischaemia (e.g. bradykinin, adenosine and reactive oxygen species).101–103 Therefore, chemical ablation of TRPV1-expressing afferents using resiniferatoxin (RTX), a potent TRPV1 agonist that induces degeneration of cardiac sensory afferents, can have potential cardioprotective effects by disrupting afferent-mediated efferent sympathetic outflow. Accordingly, chemical ablation of epicardial TRPV1 fibres through pericardial injection of RTX was shown to reduce the incidence of VA after chronic MI in a porcine model.104 Likewise, epicardial administration of RTX immediately prior to MI induction was found to prevent adverse cardiac remodelling and autonomic dysregulation by suppressing the exaggerated CSAR, attenuating heightened renal and cardiac sympathoexcitation and improving baroreflex sensitivity in a rat model of chronic heart failure.105 However, pericardial RTX can ablate both sympathetic and vagal TRPV1-expressing fibres. Ablation of these vagal afferents can further limit vagal tone in patients with SHD. Hence, targeting of sympathetic afferents specifically at the dorsal root ganglia/spinal cord or SG may have greater beneficial effects. In this regard, intrathecal administration of RTX has been investigated, demonstrating effective suppression of VA in rats, whereas administration of RTX locally to thoracic dorsal root ganglia was shown to reduce ischaemia–reperfusion-induced ventricular arrhythmogenesis in a porcine model, without affecting haemodynamic parameters.106,107 Notably, in a chronic MI pig model, epidural administration of RTX for spinal cardiac afferent ablation significantly attenuated the subsequent MI-induced autonomic remodelling, including inflammation and oxidative stress, reducing the degree of sympathoexcitation in response to nociceptive stimuli and improving ventricular electrophysiological parameters, ultimately leading to a significant reduction in VT/VF inducibility.108 Nevertheless, although TRPV1-mediated selective sympathetic deafferentation via RTX has shown promise as a therapeutic strategy for managing VA in the setting of MI, further human data are needed to elucidate its therapeutic benefit.

Bioelectrical Stimulation to Achieve Sympathetic Neuromodulation

The kilohertz frequency alternating current (KHFAC) has been reported as a neuromodulatory strategy for selectively inhibiting sympathetic afferent and efferent transmission.109 This approach involves reversible suppression of neural action potentials by continuous high-frequency electrical stimulation, resulting in a state of conduction block. However, this approach is limited by the initial sympathoexcitatory effects of stimulation prior to block, and efforts aimed at optimising stimulation protocols to mitigate the deleterious onset of these responses are on-going.110 In porcine models, KHFAC applied acutely to the paravertebral sympathetic chain effectively attenuated subsequent sympathetic stimulation-induced haemodynamic and electrophysiological alterations, whereas sympathetic block achieved by charge-balanced direct current reduced VT inducibility in chronic MI animals.111,112 Additional studies are needed to evaluate the chronic effects of KHFAC.

Restoration of Cardiac Sympathetic Innervation

As previously discussed, sympathetic denervation plays a significant role in the development of postinfarct arrhythmias by promoting electrical heterogeneity, predisposing to VA.23,26 Previous studies have demonstrated that chondroitin sulfate proteoglycans present in the cardiac scar inhibit the normal reinnervation of both the infarcted and peri-infarct myocardium by sympathetic axons.113 Interestingly, ablation of the chondroitin sulfate proteoglycan receptor, protein tyrosine phosphatase receptor s (PTPs), allowed for sympathetic axons to fully reinnervate the intact peri-infarct tissue in a mouse infarct model.114 Gardner et al. investigated how the restoration of sympathetic innervation after MI influences susceptibility to arrhythmias.114 Their approach involved targeting PTPs with pharmacological modulation initiated 3 days after MI in a mouse model, aimed at promoting reinnervation of the infarcted tissue. The restoration of sympathetic innervation resulted in a significant reduction in arrhythmia susceptibility and normalised cardiac electrophysiological properties and Ca2+ dynamics, despite the persistence of scar tissue.114 Evaluations in large-animal models and humans are needed to further determine the safety and efficacy of these small molecule therapies in restoring sympathetic innervation and providing anti-arrhythmic benefit.

Sodium–Glucose Cotransporter 2 Inhibitors, Ventricular Arrhythmias and Sudden Cardiac Death

Many heart failure therapies have been shown to reduce the risk of VAs by targeting the neurohormonal activation after MI and heart failure. Despite not targeting adrenergic receptors or angiotensin and its pathways directly, sodium–glucose cotransporter 2 (SGLT2) inhibitors are thought to have autonomic effects, and have been reported to reduce the risk of sudden cardiac death.115,116 As such, the EMBODY trial reported improvements in autonomic function, as evidenced by increased heart rate variability, in patients with type 2 diabetes receiving SGLT2 inhibitors between 2 and 12 weeks after acute MI.117 A bidirectional interplay likely exists between the sympathetic nervous system and SGLT2 regulation, characterised by sympathetic nervous system-mediated upregulation of SGLT2 expression and the sympathoinhibitory effects of SGLT2 inhibitors.118 Increasing evidence suggests that SGLT2 inhibition attenuates sympathetic activity, with reductions in sympathetic nerve activity and a significant decrease in tyrosine hydroxylase expression and NA levels noted in the kidneys of a high-fat diet-fed mouse model with SGLT2 inhibitor administration.119,120 The sympathoinhibitory effects of SGLT2 inhibitors are also postulated to arise, at least in part, from diminished renal afferent sympathetic activation.121

Other Potential Molecular Targets

Advances in high-throughput sequencing and transcriptomic analyses have identified multiple molecular pathways as potential targets for modulating sympathetic neurotransmission.122 Among these, phosphodiesterase 2A has emerged as an important regulator of calcium homeostasis and NA release within SG neurons in both rodent models and human conditions characterised by increased sympathetic activity, such as hypertension and heart failure.123 Evidence indicates that phosphodiesterase 2A may serve as a viable therapeutic target for attenuating sympathetic hyperactivity via modulation of cGMP signalling.123 Furthermore, the nitric oxide–cGMP signalling axis is subject to regulatory control by carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON), a neuronal nitric oxide synthase adaptor protein.124 CAPON could also serve as a potential target for arrhythmias, although additional studies in large-animal models of heart disease and humans are needed.124

Future Directions

Despite the increasingly established role of the ANS in the pathogenesis of VA and recent advances in the development of several neuromodulatory therapies for the treatment of these arrhythmias, significant knowledge gaps in our understanding of the complex interactions of the ANS with the heart remain. The plasticity within the ANS may also mean that stimulation or blockade at a single site may require on-going adjustments to sustain chronic efficacy. Current sympathetic neuromodulatory therapies, including cardiac sympathetic denervation and renal denervation, are relatively gross interventions that can have multisystem effects. In this regard, more targeted approaches are welcomed. Although potentially targeting NPY and its receptors, cardiac sympathetic TRPV1 afferents or restoring post-MI cardiac sympathetic reinnervation in the scar represent more targeted, novel, and exciting approaches, the feasibility, efficacy, and safety of these therapies in patients with cardiovascular disease, along with evaluation of the ideal timing for the institution of these interventions, require additional translational and human studies.

Clinical Perspective

  • Persistent sympathoexcitation and parasympathetic withdrawal create an electrophysiological substrate that predisposes to ventricular arrhythmias (VAs) in patients with structural heart disease.
  • Bedside neuromodulatory techniques, such as percutaneous stellate ganglion block and thoracic epidural anaesthesia, as well as surgical cardiac sympathetic and renal denervation, can suppress refractory ventricular arrhythmias by disrupting sympathetic input to the heart. However, their clinical utility remains limited by anaesthetic pharmacokinetics (in the case of SG block and epidural anaesthesia), anticoagulation-related contraindications, procedural risks and variable long-term durability.
  • Novel approaches, including neuropeptide Y receptor antagonists, targeted spinal nociceptive afferent ablation (e.g. resiniferatoxin), sympathetic nerve bioelectronic blockade and small molecules aimed at restoring innervation, hold promise for the durable, selective suppression of cardiac sympathetic tone. Rigorous translational and clinical evaluation is required to define the optimal timing, safety, and efficacy of these novel therapies.

References

  1. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res 2014;114:1004–21. 
    Crossref | PubMed
  2. Corr PB, Gillis RA. Autonomic neural influences on the dysrhythmias resulting from myocardial infarction. Circ Res 1978;43:1–9. 
    Crossref | PubMed
  3. Jardine DL, Charles CJ, Ashton RK, et al. Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model. J Physiol 2005;565:325–33. 
    Crossref | PubMed
  4. La Rovere MT, Bigger JT Jr, Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998;351:478–84. 
    Crossref | PubMed
  5. Ma R, Zucker IH, Wang W. Central gain of the cardiac sympathetic afferent reflex in dogs with heart failure. Am J Physiol 1997;273:H2664–71. 
    Crossref | PubMed
  6. van Weperen VYH, Ripplinger CM, Vaseghi M. Autonomic control of ventricular function in health and disease: current state of the art. Clin Auton Res 2023;33:491–517. 
    Crossref | PubMed
  7. Zipes DP, Rubart M. Neural modulation of cardiac arrhythmias and sudden cardiac death. Heart Rhythm 2006;3:108–13. 
    Crossref | PubMed
  8. Chidsey CA, Harrison DC, Braunwald E. Augmentation of the plasma nor-epinephrine response to exercise in patients with congestive heart failure. N Engl J Med 1962;267:650–4. 
    Crossref | PubMed
  9. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation 1996;94:690–7. 
    Crossref | PubMed
  10. Kalla M, Hao G, Tapoulal N, et al. The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade. Eur Heart J 2020;41:2168–79. 
    Crossref | PubMed
  11. Ullman B, Hulting J, Lundberg JM. Prognostic value of plasma neuropeptide-Y in coronary care unit patients with and without acute myocardial infarction. Eur Heart J 1994;15:454–61. 
    Crossref | PubMed
  12. Han S, Kobayashi K, Joung B, et al. Electroanatomic remodeling of the left stellate ganglion after myocardial infarction. J Am Coll Cardiol 2012;59:954–61. 
    Crossref | PubMed
  13. Ajijola OA, Hoover DB, Simerly TM, et al. Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm. JCI Insight 2017;2:e94715. 
    Crossref | PubMed
  14. Barrett MS, Bauer TC, Li MH, et al. Ischemia–reperfusion myocardial infarction induces remodeling of left cardiac-projecting stellate ganglia neurons. Am J Physiol Heart Circ Physiol 2024;326:H166–79. 
    Crossref | PubMed
  15. Salavatian S, Hoang JD, Yamaguchi N, et al. Myocardial infarction reduces cardiac nociceptive neurotransmission through the vagal ganglia. JCI Insight 2022;7:e155747. 
    Crossref | PubMed
  16. Devarajan A, Wang K, Lokhandwala ZA, et al. Myocardial infarction causes sex-dependent dysfunction in vagal sensory glutamatergic neurotransmission that is mitigated by 17β-estradiol. JCI Insight 2024;9:e181042. 
    Crossref | PubMed
  17. van Weperen VYH, Vaseghi M. Cardiac vagal afferent neurotransmission in health and disease: review and knowledge gaps. Front Neurosci 2023;17:1192188. 
    Crossref | PubMed
  18. Cao JM, Chen LS, KenKnight BH, et al. Nerve sprouting and sudden cardiac death. Circ Res 2000;86:816–21. 
    Crossref | PubMed
  19. Vracko R, Thorning D, Frederickson RG. Nerve fibers in human myocardial scars. Hum Pathol 1991;22:138–46. 
    Crossref | PubMed
  20. Inoue H, Zipes DP. Time course of denervation of efferent sympathetic and vagal nerves after occlusion of the coronary artery in the canine heart. Circ Res 1988;62:1111–20. 
    Crossref | PubMed
  21. Kammerling JJ, Green FJ, Watanabe AM, et al. Denervation supersensitivity of refractoriness in noninfarcted areas apical to transmural myocardial infarction. Circulation 1987;76:383–93. 
    Crossref | PubMed
  22. Inoue H, Zipes DP. Results of sympathetic denervation in the canine heart: supersensitivity that may be arrhythmogenic. Circulation 1987;75:877–87. 
    Crossref | PubMed
  23. Vaseghi M, Lux RL, Mahajan A, Shivkumar K. Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction. Am J Physiol Heart Circ Physiol 2012;302:h1838–46. 
    Crossref | PubMed
  24. Cao JM, Fishbein MC, Han JB, et al. Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. Circulation 2000;101:1960–9. 
    Crossref | PubMed
  25. Boogers MJ, Borleffs CJW, Henneman MM, et al. Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol 2010;55:2769–77. 
    Crossref | PubMed
  26. Fallavollita JA, Heavey BM, Luisi AJ Jr, et al. Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. J Am Coll Cardiol 2014;63:141–9. 
    Crossref | PubMed
  27. Rizas KD, Hamm W, Kääb S, et al. Periodic repolarisation dynamics: a natural probe of the ventricular response to sympathetic activation. Arrhythm Electrophysiol Rev 2016;5:31–6. 
    Crossref | PubMed
  28. Wang W, Schultz HD, Ma R. Cardiac sympathetic afferent sensitivity is enhanced in heart failure. Am J Physiol 1999;277:H812–7. 
    Crossref | PubMed
  29. Nakamura K, Ajijola OA, Aliotta E, et al. Pathological effects of chronic myocardial infarction on peripheral neurons mediating cardiac neurotransmission. Auton Neurosci 2016;197:34–40. 
    Crossref | PubMed
  30. Kanazawa H, Ieda M, Kimura K, et al. Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents. J Clin Invest 2010;120:408–21. 
    Crossref | PubMed
  31. Olivas A, Gardner RT, Wang L, et al. Myocardial infarction causes transient cholinergic transdifferentiation of cardiac sympathetic nerves via gp130. J Neurosci 2016;36:479–88. 
    Crossref | PubMed
  32. Wang L, Olivas A, Francis Stuart SD, et al. Cardiac sympathetic nerve transdifferentiation reduces action potential heterogeneity after myocardial infarction. Am J Physiol Heart Circ Physiol 2020;318:H558–65. 
    Crossref | PubMed
  33. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000;283:1295–302. 
    Crossref | PubMed
  34. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8. 
    Crossref | PubMed
  35. SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. 
    Crossref | PubMed
  36. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670–6. 
    Crossref | PubMed
  37. Baldi E, Conte G, Zeppenfeld K, et al. Contemporary management of ventricular electrical storm in Europe: results of a European Heart Rhythm Association survey. Europace 2023;25:1277–83. 
    Crossref | PubMed
  38. Yanowitz F, Preston JB, Abildskov JA. Functional distribution of right and left stellate innervation to the ventricles. Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circ Res 1966;18:416–28. 
    Crossref | PubMed
  39. Schwartz PJ. Cardiac sympathetic denervation to prevent life-threatening arrhythmias. Nat Rev Cardiol 2014;11:346–53. 
    Crossref | PubMed
  40. Vaseghi M, Yamakawa K, Sinha A, et al. Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia. Am J Physiol Heart Circ Physiol 2013;305:h1020–30. 
    Crossref | PubMed
  41. Chouairi F, Rajkumar K, Benak A, et al. A multicenter study of stellate ganglion block as a temporizing treatment for refractory ventricular arrhythmias. JACC Clin Electrophysiol 2024;10:750–8. 
    Crossref | PubMed
  42. Tian Y, Wittwer ED, Kapa S, et al. Effective use of percutaneous stellate ganglion blockade in patients with electrical storm. Circ Arrhythm Electrophysiol 2019;12:e007118. 
    Crossref | PubMed
  43. Fudim M, Qadri YJ, Waldron NH, et al. Stellate ganglion blockade for the treatment of refractory ventricular arrhythmias. JACC Clin Electrophysiol 2020;6:562–71. 
    Crossref | PubMed
  44. Savastano S, Baldi E, Compagnoni S, et al. Electrical storm treatment by percutaneous stellate ganglion block: the STAR study. Eur Heart J 2024;45:823–33. 
    Crossref | PubMed
  45. Patel RA, Condrey JM, George RM, et al. Stellate ganglion block catheters for refractory electrical storm: a retrospective cohort and care pathway. Reg Anesth Pain Med 2023;48:224–8. 
    Crossref | PubMed
  46. Sanghai S, Abbott NJ, Dewland TA, et al. Stellate ganglion blockade with continuous infusion versus single injection for treatment of ventricular arrhythmia storm. JACC Clin Electrophysiol 2021;7:452–60. 
    Crossref | PubMed
  47. Dusi V, Angelini F, Baldi E, et al. Continuous stellate ganglion block for ventricular arrhythmias: case series, systematic review, and differences from thoracic epidural anaesthesia. Europace 2024;26:euae074. 
    Crossref | PubMed
  48. Nonoguchi NM, Adachi M, Nogami A, et al. Stellate ganglion phototherapy using low-level laser: a novel rescue therapy for patients with refractory ventricular arrhythmias. JACC Clin Electrophysiol 2021;7:1297–308. 
    Crossref | PubMed
  49. Sato T, Kamada R, Koizumi T, et al. Refractory ventricular tachycardia in a patient with a left ventricular assist device successfully treated with stellate ganglion phototherapy. Can J Cardiol 2020;36:1977.e1–3. 
    Crossref | PubMed
  50. Takahashi K, Egami Y, Nishino M, Tanouchi J. Clinical impact of stellate ganglion phototherapy on ventricular tachycardia storm requiring mechanical circulatory support devices: a case report. Eur Heart J Case Rep 2024;8:ytae177. 
    Crossref | PubMed
  51. Markman TM, Pothineni NVK, Zghaib T, et al. Effect of transcutaneous magnetic stimulation in patients with ventricular tachycardia storm: a randomized clinical trial. JAMA Cardiol 2022;7:445–9. 
    Crossref | PubMed
  52. Narziev B, Yakubov A, Hamraev R, et al. A case of successful percutaneous ethanol stellate ganglion block on ventricular tachycardia storm. J Cardiol Cases 2021;23:234–7. 
    Crossref | PubMed
  53. Chatzidou S, Kontogiannis C, Tampakis K, et al. Cryoablation of stellate ganglion for the management of electrical storm: the first reported case. Europace 2021;23:1105. 
    Crossref | PubMed
  54. Rao BH, Lokre A, Patnala N, Padmanabhan TNC. Stellate ganglion ablation by conventional radiofrequency in patients with electrical storm. Europace 2023;25:euad290. 
    Crossref | PubMed
  55. Hayase J, Vampola S, Ahadian F, et al. Comparative efficacy of stellate ganglion block with bupivacaine vs pulsed radiofrequency in a patient with refractory ventricular arrhythmias. J Clin Anesth 2016;31:162–5. 
    Crossref | PubMed
  56. Batnyam U, Vlassakov KV, Halawa A, et al. Safety and efficacy of ultrasound-guided sympathetic blockade by proximal intercostal block in electrical storm patients. JACC Clin Electrophysiol 2024;10:734–46.
  57. Zinboonyahgoon N, Luksanapruksa P, Piyaselakul S, et al. The ultrasound-guided proximal intercostal block: anatomical study and clinical correlation to analgesia for breast surgery. BMC Anesthesiol 2019;19:94. 
    Crossref | PubMed
  58. Bourke T, Vaseghi M, Michowitz Y, et al. Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation. Circulation 2010;121:2255–62. 
    Crossref | PubMed
  59. Do DH, Bradfield J, Ajijola OA, et al. Thoracic epidural anesthesia can be effective for the short-term management of ventricular tachycardia storm. J Am Heart Assoc 2017;6:e007080. 
    Crossref | PubMed
  60. Hoang JD, van Weperen VYH, Kang KW, et al. Antiarrhythmic mechanisms of epidural blockade after myocardial infarction. Circ Res 2024;135:e57–75. 
    Crossref | PubMed
  61. Dusi V, Gornbein J, Do DH, et al. Arrhythmic risk profile and outcomes of patients undergoing cardiac sympathetic denervation for recurrent monomorphic ventricular tachycardia after ablation. J Am Heart Assoc 2021;10:e018371. 
    Crossref | PubMed
  62. Vaseghi M, Barwad P, Malavassi Corrales FJ, et al. Cardiac sympathetic denervation for refractory ventricular arrhythmias. J Am Coll Cardiol 2017;69:3070–80. 
    Crossref | PubMed
  63. Irie T, Yamakawa K, Hamon D, et al. Cardiac sympathetic innervation via middle cervical and stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy. Am J Physiol Heart Circ Physiol 2017;312:H392–405. 
    Crossref | PubMed
  64. Assis FR, Sharma A, Shah R, et al. Long-term outcomes of bilateral cardiac sympathetic denervation for refractory ventricular tachycardia. JACC Clin Electrophysiol 2021;7:463–70. 
    Crossref | PubMed
  65. Sridharan A, Tang A, Sorg JM, et al. Effect of bilateral cardiac sympathetic denervation on burden of premature ventricular contractions. Circ Arrhythm Electrophysiol 2023;16:e011546. 
    Crossref | PubMed
  66. Ahmed A, Charate R, Bawa D, et al. Bilateral cardiac sympathetic denervation for refractory multifocal premature ventricular contractions in patients with nonischemic cardiomyopathy. JACC Clin Electrophysiol 2024;10:31–9. 
    Crossref | PubMed
  67. Vaseghi M, Gima J, Kanaan C, et al. Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: intermediate and long-term follow-up. Heart Rhythm 2014;11:360–6. 
    Crossref | PubMed
  68. Waddell-Smith KE, Ertresvaag KN, Li J, et al. Physical and psychological consequences of left cardiac sympathetic denervation in long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol 2015;8:1151–8. 
    Crossref | PubMed
  69. Curtis B, VanAken G, Al-Sadawi M, et al. Safety and outcomes of surgical cardiac sympathetic denervation when used as salvage therapy among high-risk patients with refractory ventricular arrhythmias. J Interv Card Electrophysiol 2025;68:411–3. 
    Crossref | PubMed
  70. Cauti FM, Rossi P, Bianchi S, et al. Modified sympathicotomy in patients with refractory ventricular tachycardia and structural heart disease: a single-center experience. J Interv Card Electrophysiol 2025;68:391–9. 
    Crossref | PubMed
  71. Weiss ML, Chowdhury SI. The renal afferent pathways in the rat: a pseudorabies virus study. Brain Res 1998;812:227–41. 
    Crossref | PubMed
  72. Bradfield JS, Vaseghi M, Shivkumar K. Renal denervation for refractory ventricular arrhythmias. Trends Cardiovasc Med 2014;24:206–13. 
    Crossref | PubMed
  73. Hu W, Tu H, Wadman MC, et al. Renal denervation achieves its antiarrhythmic effect through attenuating macrophage activation and neuroinflammation in stellate ganglia in chronic heart failure. Cardiovasc Res 2025;120:2420–33. 
    Crossref | PubMed
  74. Zhang WH, Zhou QN, Lu YM, et al. Renal denervation reduced ventricular arrhythmia after myocardial infarction by inhibiting sympathetic activity and remodeling. J Am Heart Assoc 2018;7:e009938. 
    Crossref | PubMed
  75. Hori Y, Temma T, Wooten C, et al. Aorticorenal ganglion as a novel target for renal neuromodulation. Heart Rhythm 2021;18:1745–57. 
    Crossref | PubMed
  76. Linz D, Wirth K, Ukena C, et al. Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs. Heart Rhythm 2013;10:1525–30. 
    Crossref | PubMed
  77. Ukena C, Mahfoud F, Ewen S, et al. Renal denervation for treatment of ventricular arrhythmias: data from an International Multicenter Registry. Clin Res Cardiol 2016;105:873–9. 
    Crossref | PubMed
  78. Armaganijan LV, Staico R, Moreira DAR, et al. 6-month outcomes in patients with implantable cardioverter-defibrillators undergoing renal sympathetic denervation for the treatment of refractory ventricular arrhythmias. JACC Cardiovasc Interv 2015;8:984–90. 
    Crossref | PubMed
  79. Hawson J, Harmer JA, Cowan M, et al. Renal denervation for the management of refractory ventricular arrhythmias: a systematic review. JACC Clin Electrophysiol 2021;7:100–8. 
    Crossref | PubMed
  80. Bradfield JS, Hayase J, Liu K, et al. Renal denervation as adjunctive therapy to cardiac sympathetic denervation for ablation refractory ventricular tachycardia. Heart Rhythm 2020;17:220–7. 
    Crossref | PubMed
  81. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911–7. 
    Crossref | PubMed
  82. Symplicity HTN-2 Investigators, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903–9. 
    Crossref | PubMed
  83. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–401. 
    Crossref | PubMed
  84. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 2018;391:2335–45. 
    Crossref | PubMed
  85. Azizi M, Saxena M, Wang Y et al. Endovascular ultrasound renal denervation to treat hypertension: the RADIANCE II Randomized Clinical Trial. J AM Med Assoc 2023;329:651–61. 
    Crossref | PubMed
  86. Pathak A, Rudolph U, Sexena M et al. Alcohol-mediated renal denervation in patients with hypertension in the absence of medications. EuroIntervention 2023;19:602–11. 
    Crossref | PubMed
  87. Tzafriri AR, Keating JH, Markham PM, et al. Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. Sci Transl Med 2015;7:285ra65. 
    Crossref | PubMed
  88. Burnstock G. Autonomic neurotransmission: 60 years since Sir Henry Dale. Annu Rev Pharmacol Toxicol 2009;49:1–30. 
    Crossref | PubMed
  89. van Weperen VYH, Hoang JD, Jani NR, et al. Circulating noradrenaline leads to release of neuropeptide Y from cardiac sympathetic nerve terminals via activation of beta-adrenergic receptors. J Physiol 2025;603:1911–21. 
    Crossref | PubMed
  90. Herring N, Lokale MN, Danson EJ, et al. Neuropeptide Y reduces acetylcholine release and vagal bradycardia via a Y2 receptor-mediated, protein kinase C-dependent pathway. J Mol Cell Cardiol 2008;44:477–85. 
    Crossref | PubMed
  91. Heredia Mdel P, Delgado C, Pereira L, et al. Neuropeptide Y rapidly enhances [Ca2+]i transients and Ca2+ sparks in adult rat ventricular myocytes through Y1 receptor and PLC activation. J Mol Cell Cardiol 2005;38:205–12. 
    Crossref | PubMed
  92. Hoang JD, Salavatian S, Yamaguchi N, et al. Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y. JCI Insight 2020;5:e135519. 
    Crossref | PubMed
  93. Bloxsom R, Liu K, Handford C, et al. The cardiac sympathetic co-transmitter neuropeptide-Y is pro-arrhythmic in human cardiomyocytes by lengthening activation-recovery interval. Eur Heart J 2024;45(Suppl 1):ehae666.3774. 
    Crossref
  94. Herring N, Kalla M, Dall’Armellina E, et al. Pro-arrhythmic effects of the cardiac sympathetic co-transmitter, neuropeptide-Y, during ischemia–reperfusion and ST elevation myocardial infarction. FASEB J 2016;30:756.2. 
    Crossref
  95. Tang J, Liu C, Wang Z, et al. Neuropeptide Y as a prognostic biomarker in electrical storm. JACC Clin Electrophysiol 2025;11:655–63. 
    Crossref | PubMed
  96. Gibbs T, Tapoulal N, Shanmuganathan M, et al. Neuropeptide-Y levels in ST-segment-elevation myocardial infarction: relationship with coronary microvascular function, heart failure, and mortality. J Am Heart Assoc 2022;11:e024850. 
    Crossref | PubMed
  97. Herring N, Tapoulal N, Kalla M, et al. Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction. Eur Heart J 2019;40:1920–9. 
    Crossref | PubMed
  98. Cuculi F, Herring N, De Caterina AR, et al. Relationship of plasma neuropeptide Y with angiographic, electrocardiographic and coronary physiology indices of reperfusion during ST elevation myocardial infarction. Heart 2013;99:1198–203. 
    Crossref | PubMed
  99. Van Weperen VY, Hoang JD, Jani NR, et al. Electrophysiological effects of sympathoexcitation are mitigated by blockade of neuropeptide Y Y2 receptors on cardiac parasympathetic nerve terminals. Circulation 2022;146(Suppl 1):Abstract 11494. 
    Crossref
  100. Jani NR, van Weperen VYH, Ayagama T, et al. Sympathovagal crosstalk: Y2-receptor blockade enhances vagal effects which in turn Reduce NPY levels via muscarinic receptor activation. Cardiovasc Res 2025. In press. 
    Crossref
  101. Pan HL, Chen SR. Sensing tissue ischemia: another new function for capsaicin receptors? Circulation 2004;110:1826–31. 
    Crossref | PubMed
  102. Uchida Y, Murao S. Bradykinin-induced excitation of afferent cardiac sympathetic nerve fibers. Jpn Heart J 1974;15:84–91. 
    Crossref | PubMed
  103. Schultz HD, Ustinova EE. Capsaicin receptors mediate free radical-induced activation of cardiac afferent endings. Cardiovasc Res 1998;38:348–55. 
    Crossref | PubMed
  104. Yoshie K, Rajendran PS, Massoud L, et al. Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction. JCI Insight 2020;5:e124477. 
    Crossref | PubMed
  105. Wang HJ, Wang W, Cornish KG, et al. Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure. Hypertension 2014;64:745–55. 
    Crossref | PubMed
  106. Wu Y, Hu Z, Wang D, et al. Resiniferatoxin reduces ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord in rats. Eur J Pharmacol 2020;867:172836. 
    Crossref | PubMed
  107. Yamaguchi T, Salavatian S, Kuwabara Y, et al. Thoracic dorsal root ganglion application of resiniferatoxin reduces myocardial ischemia-induced ventricular arrhythmias. Biomedicines 2023;11:2720. 
    Crossref | PubMed
  108. van Weperen V, Hoang J, Chan C, et al. Bs-469619-001 Spinal afferent denervation ameliorates pathological autonomic remodeling and reduces ventricular arrhythmias after chronic myocardial infarction. Heart Rhythm 2024;21(Suppl):S51–2. 
    Crossref
  109. Fjordbakk CT, Miranda JA, Sokal D, et al. Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig. Sci Rep 2019;9:18136. 
    Crossref | PubMed
  110. Hadaya J, Buckley U, Gurel NZ, et al. Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control. Am J Physiol Heart Circ Physiol 2022;322:H105–15. 
    Crossref | PubMed
  111. Buckley U, Chui RW, Rajendran PS, et al. Bioelectronic neuromodulation of the paravertebral cardiac efferent sympathetic outflow and its effect on ventricular electrical indices. Heart Rhythm 2017;14:1063–70. 
    Crossref | PubMed
  112. Chui RW, Buckley U, Rajendran PS, et al. Bioelectronic block of paravertebral sympathetic nerves mitigates post-myocardial infarction ventricular arrhythmias. Heart Rhythm 2017;14:1665–72. 
    Crossref | PubMed
  113. Gardner RT, Habecker BA. Infarct-derived chondroitin sulfate proteoglycans prevent sympathetic reinnervation after cardiac ischemia–reperfusion injury. J Neurosci 2013;33:7175–83. 
    Crossref | PubMed
  114. Gardner RT, Wang L, Lang BT, et al. Targeting protein tyrosine phosphatase sigma after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nat Commun 2015;6:6235. 
    Crossref | PubMed
  115. Basile P, Monitillo F, Santoro D, et al. Impact on ventricular arrhythmic burden of SGLT2 inhibitors in patients with chronic heart failure evaluated with cardiac implantable electronic device monitoring. J Cardiol 2025;85:229–34. 
    Crossref | PubMed
  116. Liao J, Ebrahimi R, Ling Z, et al. Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of >80,000 patients (the SGLT2i-Arrhythmias and Sudden Cardiac Death). Cardiovasc Diabetol 2024;23:78. 
    Crossref | PubMed
  117. Shimizu W, Kubota Y, Hoshika Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol 2020;19:148. 
    Crossref | PubMed
  118. Herat LY, Magno AL, Rudnicka C, et al. SGLT2 Inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl Sci 2020;5:169–79. 
    Crossref | PubMed
  119. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci 2020;5:632–44. 
    Crossref | PubMed
  120. Matthews VB, Elliot RH, Rudnicka C, et al. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens 2017;35:2059–68. 
    Crossref | PubMed
  121. Sano M. Sodium glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation. Ther Adv Cardiovasc Dis 2020;14:1753944720939383. 
    Crossref | PubMed
  122. Herring N, Kalla M, Paterson DJ. The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies. Nat Rev Cardiol 2019;16:707–26. 
    Crossref | PubMed
  123. Liu K, Li D, Hao G, et al. Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity. JCI Insight 2018;3:e98694. 
    Crossref | PubMed
  124. Chang KC, Barth AS, Sasano T, et al. CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart. Proc Natl Acad Sci USA 2008;105:4477–82. 
    Crossref | PubMed
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