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

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.

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.

Principal current sympathetic neuromodulatory therapies are framed in black, whereas novel potential neuromodulatory targets are framed in red. β₁R = β₁-adrenoceptor; ACh = acetylcholine; M₂R = muscarinic M₂ receptor; NA = noradrenaline; NPY = neuropeptide Y; RTX = resiniferatoxin (results in nociceptive sensory neuronal ablation); Y₁R = NPY Y₁ receptor; Y₂R = NPY Y₂ receptor.

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.

Funding Statement

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