Preface Editorial for Special Issue Dedicated to Jeffrey L. Ardell (1952–2025) Cardiac Neurobiology: Concepts to Clinic

Abstract

In 2016, we published a special issue concerned with cardiac autonomic control in health and disease (Shivkumar & Ardell, 2016). Since then, there has been an explosion of scientific interest in the neurobiology of the cardiac autonomic nervous system (Herring et al., 2019; Paton et al., unpublished raw data) aimed at understanding how neuromodulation can be used therapeutically to treat cardiac disease (La Rovere et al., 2020; Hanna, Buch et al., 2021; Hadaya & Ardell, 2020). To bridge the areas of neurology and cardiology, the emerging field of neurocardiology and bioelectronic medicine or ‘neuroceutics’ is now receiving significant attention and funding as a priority area from NIH (National Institutes of Health, and Office of Strategic Coordination-The Common Fund. Stimulating Peripheral Activity to Relieve Conditions – SPARC; the University of Minnesota awarded $21 million to lead research revealing effects of vagus nerve stimulation in humans) and the Leducq Foundation (Paterson & Shivkumar, 2023). The strategy is underpinned by the development of personalised site-specific targeting of the nervous system to treat end-organ function, in particular arrhythmia. What is becoming apparent is the importance of bidirectional communication between neurons and myocytes (Davis et al., 2022) and the need to have a better understanding of the complex neural architecture (Hanna, Dacey et al., 2021; Rajendran et al., 2019) that underpins rhythm disturbance from the ‘little brain’ in the heart (Armour 2008; Herring & Paterson, 2021). Moreover, a deeper appreciation of neural circuits and the development of miniaturization of sensor technology has provided an opportunity to lay the foundations for the next generation of bioelectronics for closed loop neuromodulation (Lerman et al., 2025).

In July 2024 The Journal of Physiology supported a focused meeting in Oxford that was associated with the International Society for Autonomic Neuroscience (ISAN 2024). This 2-day meeting provided a framework to assemble opinion leaders in the field and also facilitated the opportunity for younger investigators from the bioengineering, physiological and medical communities to interact. In this special issue, entitled Cardiac Neurobiology: Concepts to Clinic, we highlight the deliberations from this meeting. In particular, the issue starts with an update on the three white papers we published in 2016, which gather the opinions of 52 leading experts in the field as they review the major advances that have taken place in the past 8 years.

The first white paper by Habecker et al. (2025) addresses the molecular and cellular basis of neural cardiac interactions in heart disease. A particular focus on novel intracellular pathways and neuroplasticity is explored, given the advances in spatial transcriptomics, and the interface to patient-specific stem cells that provides a pathophysiological contextualization to study ‘disease in a dish’. The use of stem cells is further highlighted with an in-depth topical review from Wu et al. (2025) that discusses the current progress and future prospects of this platform. The utility of this approach is illustrated by Mohammadi et al. (2025) who observed that sympathetic neurons can induce a more mature phenotype in IPSC-derived cardiac myocytes, reinforcing the notion of cross-talk communication between neurons and myocytes. Mapping these technologies for translational advancements is featured in the second white paper (Herring et al., 2025), which explores our emerging understanding of where and how to target key sites for neuromodulation (intracardiac nervous system, stellate ganglia, vagus nerve, dorsal root ganglia and the mid-brain nuclei in the brain that are cardiovascular active). The challenge here is to use the body's on-board ‘homeostatic intelligence system’ so that closed-loop autonomic regulation therapies can evolve. As Herring, Ardell and colleagues discuss, this will only be achieved with a viable bioengineering strategy that develops sensor technology to respond to appropriate physiological biomarkers (both electrical and mechanical) that can work with endogenous control systems to optimize outcomes rather than in opposition to them.

The translational significance of neuromodulation as a therapy will need to pass from the dish to a pre-clinical environment.

Importantly, this transition will have to demonstrate a patient-specific utility with positive outcomes over and above traditional pharmacological interventions if clinical reach is to be achieved. This point is the focus of the third extensive white paper by Ajijola et al. (2025). Here, they discuss the challenges and opportunities of clinical neurocardiology and define the value of neuroscience-based cardiovascular therapeutics. They present updates on major clinical trials involving neuromodulation therapy and the value of novel autonomic biomarkers that hold promise as prognostic indicators.

Emerging evidence is now highlighting a role of neuropeptide Y (NPY) as one prognostic biomarker post-myocardial infarction (MI) (Kalla et al., 2020). This neuropeptide is co-released with noradrenaline (NA) during states of high sympathetic drive, and its importance has been highlighted by Neil Herring in his Bayliss Starling Prize lecture (Bussmann et al., 2023) and in the article by van Weperen et al. (2025) where they elegantly showed circulating NA leads to the release of NPY from cardiac sympathetic nerves via activation of postganglionic pre-synaptic beta-adrenergic receptors. The release of NA is probably further involved in a positive feedback cascade to cause more transmission of both NA (Adler-Graschinsky & Langer, 1975) and NPY because NA and indeed adrenaline are released in diseased post-ganglionic sympathetic nerves and bind to pre-synaptic beta-2 adrenergic receptors (Bardsley et al., 2018). In a paper by Vrabec et al. (2025), modulation of sympathetic hyperexcitability in disease through a bioelectronic block of stellate ganglia has been shown to mitigate the pacing-induced heterogeneous release of catecholamine and NPY in the infarcted pig heart. This work highlights the potential of axonal modulation therapy to titrate direct current block to modulate neuronal excitability in a highly controllable fashion.

The importance of relating structure to function for cardiac neuromodulation is reviewed in a timely fashion by Qu et al. (2025) where they link ultrastructure at different scales to impulse conduction and arrhythmogenesis. Here, they present a framework of the experimental data needed to validate multiscale models and provide an increased predictability of these models to better understand cardiac conduction and arrhythmogenesis. A further study by Ashton et al. (2025) illustrates the importance of the 3-D structural and electrophysiological functional changes in intracardiac neurons that have been linked to increased excitability associated with atrial fibrillation (AF). Similarly, the use of computational modelling of cardiac control, following MI using an in silico patient cohort, has been employed by Gee et al. (2025) to help explain patient heterogeneity of vagal baroreflex control after ischaemic injury. Interestingly, it is reported that individuals with central or peripheral vagal efferent adaptation and preserved baroreceptor gain could maintain high baroreflex sensitivity post-MI.

Although the vagus nerve can promote AF, it can also be anti-arrhythmic in the ventricle because it behaves like nature's calcium channel blocker, which is why there have been extensive efforts to understand its properties and how to target its selectively. Thompson et al. (2025) undertook an anatomical and functional investigation looking at the organization of cardiac fibres in the porcine cervical vagus nerve with the aim of developing a strategy for spatially selective efferent neuromodulation. A landmark study from the Macefield laboratory (Farmer et al., 2025) describes the firing properties of single axons with cardiac rhythmicity in the human cervical vagus nerve. The electrical signatures observed illustrated the heterogeneity of firing patterns to the cardiac cycle and the opportunity to understand how neural patterning evolves in health and disease.

Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress-related arrhythmic sudden death. Vanaja et al. (2025) from the Zaglia and Mongillo group have identified that cardiac sympathetic neurons are additional cells affected in a genetically determined mouse model of arrhythmogenic cardiomyopathy linked to mutations in desmoglein-2. Altered sympathetic innervation and patterning is now becoming recognized as a characteristic of arrhythmogenic cardiomyopathy that may contribute to the aetiology of the disease itself. Indeed, neural remodelling is also a feature in many primary cardiovascular diseases such as hypertension. Here, Li et al. (2025) from the Habecker group showed that high blood pressure increases sympathetic neuron activity by enhancing intraganglionic cholinergic collateral connections in the stellate ganglion. This work demonstrates that significant neuroplasticity also occurs in the peripheral nervous system and contributes to sympathetic dysautonomia. Similarly, Ahmadian et al. (2025) observed that a single session of acute intermittent hypoxia (IH) is capable of neuromodulating the heart in a rat model of spinal cord injury where there is a disrupted bulbospinal sympathetic pathway. Whether IH has the therapeutic utility in a similar patient group remains to be determined, but earlier studies reported that IH can increase post ganglionic sympathetic activity by decreasing the inhibitory action of the NO-cGMP pathway on sympathetic drive (Mohan et al., 2001).

Going forward, one of the key challenges is to develop model systems that reproducibly recapitulate the human phenotype to provide clinical contextualization. To this end, the development of human IPSC and 3-D organoid models will aid in this endeavour, especially in disease states that have a strong genetic underpinning such as channelopathies. Moreover, the utilization of other mammalian models will be important to show the conservation of key molecular and cellular structures from transcripts to proteins to determine whether the human function can be mimicked (Habecker et al., 2025; Paton et al., unpublished raw data). In the paper by Tompkins et al. (2025), a detailed structural and electrophysiological investigation is described that looked at the comparative specialization of intrinsic cardiac neurons (ICNs) in humans, mice and pigs. Here, they found both conserved and derived attributes of these neurons within mammals that enhance our understanding of the complex circuitry of the ICN for neuromodulation therapy in conditions such as AF. Combined with a computational approach using single-cell transcriptomics, Gupta et al. (2025) modelled neurons in the heart's ‘little brain’ and identified that each neuronal genotype was characterized by a unique combination of ion channels that are mapped onto a specific transcriptomic signature.

In past 10 years, significant progress has been made in bridging the concept of neuromodulation therapy to the clinic. There is still much to do, and it will be important to demonstrate that targeting the cardiac autonomic nervous system results in enhanced efficacy of therapy over contemporary interventions to change clinical practice. Closing the gap on the bioelectronic interface to cell-based therapies with technological advances in bionanomaterials presents a unique opportunity to bring together the community of bioengineers, physiologists and physicians. Our mission is to build the next generation of therapies that precisely target the wiring of the nervous system and help save the lives of millions who die every year of cardiac arrest.

Indeed, in 2016, the editorial coauthored by the late Professor Ardell (Shivkumar & Ardell, 2016) concluded, ‘Neuromodulation based strategies provide unique opportunities to develop meaningful therapies for the tens of millions who are going to die suddenly from arrhythmias or suffer serious morbidity and ultimate death due to heart failure in the coming years!’ This promise has already started to bear fruits based on the progress reported in this issue. We can now state that the future possibilities for therapies through a better understanding of physiology is indeed very bright.

This special issue is dedicated to Jeff Ardell, our close friend and colleague, who was a pioneer and advocate in the field of the neurocardiology. He will be sadly missed, but his legacy will live on in his pupils, colleagues and research papers he authored. In Piam Memoriam.