The role of ganglionic plexi neurons in atrial fibrillation following spinal cord injury

The intrinsic cardiac nervous system (ICNS) consists of a sophisticated network of neurons and ganglia embedded within the heart. This system plays a vital role in regulating cardiac function by integrating autonomic inputs and modulating heart rate, rhythm and contractility to sustain cardiovascular homeostasis. In intact physiology, the ICNS can operate independently of co-ordinating supraspinal input. Key components of the ICNS include pacemaker cells of the sinoatrial node and ganglionated plexi (GP) neurons, which are crucial for orchestrating the electrical activity of the heart in response to physiological perturbations. Atrial fibrillation (AF), a prevalent and complex arrhythmia, disrupts this stability and is associated with significant morbidity and mortality (Avazzadeh et al., 2020). Research suggests a strong link between altered autonomic activity, abnormal GP neuron physiology and the development and perpetuation of AF (Avazzadeh et al., 2020). Although the role of the sinoatrial node in regulating heart rate and its involvement in AF is well-understood, the precise physiological properties of human GP neurons and their changes in the context of AF remain poorly characterized. Moreover, autonomic nervous system remodelling in the human atria probably occurs in several other significant conditions associated with AF, including obesity, heart failure, hypertension, obstructive sleep apnoea, chronic obstructive pulmonary disease and ageing. Understanding these differences could provide insight into the pathophysiology of AF and help identify potential therapeutic targets. A recent paper published in The Journal of Physiology by Ashton et al. (2025) addresses gaps in our understanding of the electrophysiological properties and 3-D structure of human right atrial GP neurons in patients with and without AF. Ashton et al. (2025) collected surgical cardiac epicardial adipose tissue biopsies from patients undergoing open-heart surgery. Adipose tissue samples were excised from the right atrial ganglionated plexus and used to identify GP neurons. Whole-cell patch clamp techniques were utilized to characterize the passive membrane properties, firing patterns and action potential frequency of GP neurons. For structural analysis, tissue clearing, immunohistochemistry and 3-D confocal microscopy were performed on fixed epicardial adipose samples to conduct phenotypic analyses of GP neurons. The tissue clearing was followed by immunostaining with primary antibodies against synapsin 1, tyrosine hydroxylase and vesicular acetylcholine transporter. These markers identified synaptic structures (i.e. synapsin 1) and differentiated between adrenergic (i.e. tyrosine hydroxylase), cholinergic (i.e. vesicular acetylcholine transporter) and dual-phenotype neurons. Intracellular dye-filling techniques uncovered significant morphological differences between human GP neurons and those previously documented in rodent GP neurons. Compared to rodent GP neurons, human GP neurons demonstrated a substantial increase in neuronal complexity and had a different morphology, being multipolar rather than unipolar. Human GP neurons displayed varied and extensive neurite branching and outgrowth, with multiple primary neurites extending from the soma, indicating more complex connectivity within and between GPs. Structurally, synapsin 1 puncta density, volume and area were significantly higher in GP neurons of AF patients, indicating increased synaptic input and extensive connectivity. Phenotypic analysis revealed fewer cholinergic and dual-phenotype neurons but increased noradrenergic neurons in GP neurons from AF patients. Electrophysiological assessments also revealed that, although passive membrane properties, action potential kinetics and after-hyperpolarization decay showed no significant differences between AF and non-AF patients, there were notable functional changes in the GP neurons of AF patients. Specifically, these neurons exhibited higher action potential firing frequencies and a lower current threshold needed to generate an action potential, indicating increased excitability. Additionally, neurons that maintain their firing rate despite continuous or repetitive stimulation were more prevalent in GP neurons from AF patients, suggesting a higher propensity for sustained high-frequency firing. Given that ablation of GP neurons has been shown to relieve AF in most cases (Avazzadeh et al., 2020), the increase in excitability and synaptic connectivity observed in the GP neurons of AF patients may explain this therapeutic mechanism. These findings indicate that targeting these specific neuronal changes could potentially enhance and refine therapeutic strategies for AF. Given that GP neurons are considered the integrating centre of the cardiac autonomic nervous system (Avazzadeh et al., 2020), a deeper understanding of their physiology in pathological conditions is highly valuable. Exploring their function in conditions such as spinal cord injury (SCI), heart failure, hypertension, obstructive sleep apnoea and obesity could yield crucial insights into disease mechanisms and therapeutic targets. Of those diseases, the cardiovascular effects of SCI might be considered a more underexplored area in terms of public awareness and research funding. SCI not only disrupts motor and sensory pathways but also (less commonly known in the general public) interferes with the autonomic control exerted on the heart. To our knowledge, although SCI significantly elevates the risk of AF (Wang et al., 2016), no studies have examined GP neuron activity in SCI patients. In this context, the research conducted by Ashton et al. (2025) on able-bodied people provides foundational insights into how pathological conditions could affect neural communication within the human intrinsic cardiac nervous system. By contrast to other autonomic dysfunctions that are more common in high-level SCI (Phillips & Krassioukov, 2015), the higher prevalence of AF in SCI patients is consistent across different levels of injury (Wang et al., 2016). This suggests that disruption of the supraspinal input onto the sympathetic preganglionic neurons from T1–T5 in the spinal cord may not be the primary contributor to the genesis of AF. Considering the dual branches of the extrinsic cardiac nervous system (i.e. the brainstem's vagus nerve and the sympathetic preganglionic neurons of the spinal cord), this apparent independence to the level of injury directs attention to vagal input onto GP neurons. AF has a complex aetiology, where vagal nerve stimulation can exhibit both pro-arrhythmogenic and anti-arrhythmogenic effects on atrial tissue (Kharbanda et al., 2022). The overall level of activity of the vagus nerve may, therefore, also be irrelevant in AF development; instead, alterations in the physiology of GP neurons might be a result of a more subtle change in the parasympathetic autonomic nervous system. Despite the vagus nerve remaining morphologically intact post-SCI, evidence indicates that parasympathetic cardiovagal control may be altered. Increased arterial stiffness post-SCI, probably a cause of prolonged inactivity, arterial shear stress, arterial wall thickening and fibrotic remodelling, is linked to a ∼50% reduction in cardiovagal baroreflex sensitivity, impairing cardiovascular regulation (Phillips & Krassioukov, 2015). Given the intricate aetiology of AF, the potential alteration of the parasympathetic cardiovagal control in SCI (Phillips & Krassioukov, 2015) and the emerging evidence linking the altered physiology of GP neurons to AF (Avazzadeh et al., 2020), an exploration of the role of GP neurons in SCI is particularly compelling. Investigating this could reveal how changes in GP neuron connectivity and physiology may contribute to the pathogenesis of AF. The study reported by Ashton et al. (2025) advances our understanding of AF by emphasizing human translation and highlighting differences between pre-clinical and clinical models. The findings on GP neuron changes in AF patients raise numerous questions regarding their physiology in autonomic issues as a result of SCI. Future research should focus on characterizing GP neuron connectivity post-SCI to explore cellular and molecular physiopathology differences and help identify new therapeutic targets. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of this work. All persons designated as authors qualify for authorship and all those who qualify for authorship are listed. No funding was received. We thank Dr Anthony Incognito, Dr Jordan Lee, Donovan B. Smith and Dr Aaron Phillips for providing insight and discussion on our manuscript.