The heart has long been viewed as a mechanical pump, but modern science increasingly recognises it as a sophisticated sensory organ deeply integrated into the nervous system. Long before the autonomic nervous system was discovered, William Harvey (Warden of Merton College, 1645) had appreciated that the heart was not an island to itself but was linked to emotional state. This connection is embedded in folklore with sayings (‘heart felt’, ‘scared to death’, ‘died of a broken heart’, ‘follow your heart, but take your brain with you’, ‘my head says one thing, my heart says another’) dating back to da Vinci (‘Tears come from the heart and not from the brain’) alongside leading 21st century figures (‘A good head and a good heart are always a formidable combination’ attributed to Nelson Mandela). Is this ‘neuro-mythology’ or does it have a neurobiological basis that represents a therapeutic opportunity?
The intrinsic cardiac nervous system (ICNS), often referred to as the “heart’s little brain” is a complex network of neurons and ganglia located on the heart’s surface that can process information and regulate cardiac function independently of the central nervous system. The neurophysiology of this predominantly sensory system is still poorly understood. Exploring the “neuro-cardiac axis”—the bidirectional communication between the brain and the heart has resulted in the emerging field of neurocardiology, where targeting the autonomics with bioelectronics and gene transfer strategies is becoming a transformative therapeutic approach to treat end organ function.
Surgical denervation of the sympathetic nervous system is not new and was first performed in 1889 to treat epilepsy. Indeed, cardiac stelletomy was popular over a century ago to treat uncontrollable angina and tachycardia but eventually fell out of favour due to variable outcomes (e.g. Horner’s syndrome) and the emergence of pharmacological therapies (such as β-blockers), coronary artery bypass surgery and percutaneous coronary interventions. It re-emerged again in the 1980’s when the electrophysiological link was made between the sympathetic nervous system and afterdepolarisation in patients with long-QT syndrome (LQT) and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the binary nature of the intervention is still viewed as sub-optimal, whereas neuromodulation of cardiac excitability may better facilitate maintenance of homeostatic control during physiological stress.
Bioelectronic Medicine: From Drugs to ‘Neuroceutics’
By bridging the gap between biology and electronics, bioelectronics for neurocardiology is shifting the paradigm in the treatment of arrhythmias from blunt electrical shocks to sophisticated, neural-based regulation by tapping into the body’s onboard homeostatic control system.
Targeted Therapy: Unlike drugs, which affect the entire body and often cause side effects, bioelectronic interventions can precisely target specific sites like the vagus nerve or the stellate ganglia to improve heart rhythm without significant systemic impact. Bioelectronic medicine, or “neuroceutics,” represents a shift from traditional pharmacology to the use of implantable devices that read and write electrical signals to the nervous system. Instead of treating the end organ directly the strategy to modulate post ganglionic pre-synaptic neurotransmission is now gaining therapeutic utility. This is based on the observation that many of the primary cardiac diseases, especially inherited arrhythmia syndromes are also diseases of the autonomic nervous system (dysautonomia) resulting in sympatho-vagal imbalance. This neural phenotype is a powerful negative prognostic indicator to trigger arrhythmic death. Moreover, emerging evidence using ‘disease in dish models’ of human derived pluripotent stem cells (hiPSC) with established genotypes (LQT and CPVT) have identified a component of the molecular and cellular impairment of these cardiac channelopathies also resides in the sympathetic neuron.
How can we target the cardiac sympathetic?Although the cardiac vagus is often referred to as nature’s calcium blocker against the sympathetic nervous system, it is notoriously difficult to regulate pharmacologically and its neuromodulation has yielded mixed results in clinical trials. Hence recent research has predominately focused on decreasing sympathetic excitability. One approach is to develop closed-loop systems, which is the focus of a recent Leducq Transatlantic Network of Excellence team that brings together bioengineers, physician scientists, computer scientists, material scientists and electrophysiologists.
Here implantable sensors (that can be dissolvable) monitor real-time physiological biomarkers (like neurotransmitter release) and automatically adjust electrical stimulation to restore autonomic balance. The future of the field is pointed towards the integration of artificial intelligence (AI) and miniaturised, organ-conformal sensors. By leveraging machine learning to decode complex neural patterns, future bioelectronic medicines aim to provide personalised, “auto-tuned” care for patients with dysautonomia.
Combining advances in Bluetooth technology facilitates real-time device readout, effectiveness and feedback dosing of neuroceutical devices. It also provides the opportunity for pattern recognition algorithms via cloud-based servers to continuously monitor cardiac rhythm to alert medical teams to potentially life-threatening electrical signals. However, several challenges remain. Biocompatibility: Long-term stable coupling between electronic materials and dynamic heart tissue is difficult to maintain. Selectivity: Current electrodes often stimulate broad nerve bundles, leading to off-target effects. Finer “intraneural” interfaces are needed for more specific signalling. Miniaturisation: Reducing device size for percutaneous (through the skin) delivery remains a priority to minimize surgical risks. Bionetwork security: preventing the hacking of signals by third parties driving interference into stimulation parameters.
Use of targeted gene therapy into the stellate to take down sympathetic excitability with cell specific viral vectors has shown viable utility in pre-clinical models, akin to a smart pre-synaptic beta blocker. Indeed, the cell to bioelectronic interface is emerging as a therapeutic strategy alongside the autografting of novel biomaterials into the autonomic nervous system to regulate neuronal firing with closed-loop bioelectronics.
In conclusion, the heart is no longer just a pump to be repaired, but a node in a vast neural network to be recalibrated. This recalibration presents an opportunity to optimise cardiac rhythm via neural targeting to modulate transmission to minimise arrhythmogenic triggers. Challenges remain but the technology is positioned to advance therapy in a precise and personalised way.
Further reading
Paterson DJ, Shivkumar K. Bioelectronics for neurocardiology: diagnosis and therapeutics. European Heart Journal (9 November 2023) doi.org/10.1093/euroheartj/ehad624
Herring N, Kalla M, Paterson DJ (2019). The Autonomic Nervous System and Cardiac Arrhythmias: Current Concepts and Emerging Therapies. Nat Rev Cardiol 16, pages 707–726 doi: 10.1038/s41569-019-0221-2
Paton JFR, Zera T, Vadigepalli R, Herring N, Paterson DJ (2026). Multimodal, device-based therapeutic targeting of the cardiovascular autonomic nervous system. Nat Rev Cardiol. 23, pages 255–278. doi.org/10.1038/s41569-025-01212-4
Li N, Zhang C, Xu M Choi Y, Sidarta-Oliveira D, Dong R, Hu X, Toledo EM, Prada-Medina CA, Argus F, Liu K, Li M, Zhou L, Bayley H, Smith C, Denning C, Domingos AI, Hao G, Li D, Paterson DJ (2026). Human-derived cardiac-neural microtissues reveal catecholaminergic polymorphic ventricular tachycardia is also a disease of the sympathetic neuron. J Physiol (15February). doi.org/10.1113/JP290024
The heart has long been viewed as a mechanical pump, but modern science increasingly recognises it as a sophisticated sensory organ deeply integrated into the nervous system. Long before the autonomic nervous system was discovered, William Harvey (Warden of Merton College, 1645) had appreciated that the heart was not an island to itself but was linked to emotional state. This connection is embedded in folklore with sayings (‘heart felt’, ‘scared to death’, ‘died of a broken heart’, ‘follow your heart, but take your brain with you’, ‘my head says one thing, my heart says another’) dating back to da Vinci (‘Tears come from the heart and not from the brain’) alongside leading 21st century figures (‘A good head and a good heart are always a formidable combination’ attributed to Nelson Mandela). Is this ‘neuro-mythology’ or does it have a neurobiological basis that represents a therapeutic opportunity?
The intrinsic cardiac nervous system (ICNS), often referred to as the “heart’s little brain” is a complex network of neurons and ganglia located on the heart’s surface that can process information and regulate cardiac function independently of the central nervous system. The neurophysiology of this predominantly sensory system is still poorly understood. Exploring the “neuro-cardiac axis”—the bidirectional communication between the brain and the heart has resulted in the emerging field of neurocardiology, where targeting the autonomics with bioelectronics and gene transfer strategies is becoming a transformative therapeutic approach to treat end organ function.
Surgical denervation of the sympathetic nervous system is not new and was first performed in 1889 to treat epilepsy. Indeed, cardiac stelletomy was popular over a century ago to treat uncontrollable angina and tachycardia but eventually fell out of favour due to variable outcomes (e.g. Horner’s syndrome) and the emergence of pharmacological therapies (such as β-blockers), coronary artery bypass surgery and percutaneous coronary interventions. It re-emerged again in the 1980’s when the electrophysiological link was made between the sympathetic nervous system and afterdepolarisation in patients with long-QT syndrome (LQT) and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the binary nature of the intervention is still viewed as sub-optimal, whereas neuromodulation of cardiac excitability may better facilitate maintenance of homeostatic control during physiological stress.
Bioelectronic Medicine: From Drugs to ‘Neuroceutics’
By bridging the gap between biology and electronics, bioelectronics for neurocardiology is shifting the paradigm in the treatment of arrhythmias from blunt electrical shocks to sophisticated, neural-based regulation by tapping into the body’s onboard homeostatic control system.
Targeted Therapy: Unlike drugs, which affect the entire body and often cause side effects, bioelectronic interventions can precisely target specific sites like the vagus nerve or the stellate ganglia to improve heart rhythm without significant systemic impact. Bioelectronic medicine, or “neuroceutics,” represents a shift from traditional pharmacology to the use of implantable devices that read and write electrical signals to the nervous system. Instead of treating the end organ directly the strategy to modulate post ganglionic pre-synaptic neurotransmission is now gaining therapeutic utility. This is based on the observation that many of the primary cardiac diseases, especially inherited arrhythmia syndromes are also diseases of the autonomic nervous system (dysautonomia) resulting in sympatho-vagal imbalance. This neural phenotype is a powerful negative prognostic indicator to trigger arrhythmic death. Moreover, emerging evidence using ‘disease in dish models’ of human derived pluripotent stem cells (hiPSC) with established genotypes (LQT and CPVT) have identified a component of the molecular and cellular impairment of these cardiac channelopathies also resides in the sympathetic neuron.
How can we target the cardiac sympathetic?Although the cardiac vagus is often referred to as nature’s calcium blocker against the sympathetic nervous system, it is notoriously difficult to regulate pharmacologically and its neuromodulation has yielded mixed results in clinical trials. Hence recent research has predominately focused on decreasing sympathetic excitability. One approach is to develop closed-loop systems, which is the focus of a recent Leducq Transatlantic Network of Excellence team that brings together bioengineers, physician scientists, computer scientists, material scientists and electrophysiologists.
Here implantable sensors (that can be dissolvable) monitor real-time physiological biomarkers (like neurotransmitter release) and automatically adjust electrical stimulation to restore autonomic balance. The future of the field is pointed towards the integration of artificial intelligence (AI) and miniaturised, organ-conformal sensors. By leveraging machine learning to decode complex neural patterns, future bioelectronic medicines aim to provide personalised, “auto-tuned” care for patients with dysautonomia.
Combining advances in Bluetooth technology facilitates real-time device readout, effectiveness and feedback dosing of neuroceutical devices. It also provides the opportunity for pattern recognition algorithms via cloud-based servers to continuously monitor cardiac rhythm to alert medical teams to potentially life-threatening electrical signals. However, several challenges remain. Biocompatibility: Long-term stable coupling between electronic materials and dynamic heart tissue is difficult to maintain. Selectivity: Current electrodes often stimulate broad nerve bundles, leading to off-target effects. Finer “intraneural” interfaces are needed for more specific signalling. Miniaturisation: Reducing device size for percutaneous (through the skin) delivery remains a priority to minimize surgical risks. Bionetwork security: preventing the hacking of signals by third parties driving interference into stimulation parameters.
Use of targeted gene therapy into the stellate to take down sympathetic excitability with cell specific viral vectors has shown viable utility in pre-clinical models, akin to a smart pre-synaptic beta blocker. Indeed, the cell to bioelectronic interface is emerging as a therapeutic strategy alongside the autografting of novel biomaterials into the autonomic nervous system to regulate neuronal firing with closed-loop bioelectronics.
In conclusion, the heart is no longer just a pump to be repaired, but a node in a vast neural network to be recalibrated. This recalibration presents an opportunity to optimise cardiac rhythm via neural targeting to modulate transmission to minimise arrhythmogenic triggers. Challenges remain but the technology is positioned to advance therapy in a precise and personalised way.
Further reading
Paterson DJ, Shivkumar K. Bioelectronics for neurocardiology: diagnosis and therapeutics. European Heart Journal (9 November 2023) doi.org/10.1093/euroheartj/ehad624
Herring N, Kalla M, Paterson DJ (2019). The Autonomic Nervous System and Cardiac Arrhythmias: Current Concepts and Emerging Therapies. Nat Rev Cardiol 16, pages 707–726 doi: 10.1038/s41569-019-0221-2
Paton JFR, Zera T, Vadigepalli R, Herring N, Paterson DJ (2026). Multimodal, device-based therapeutic targeting of the cardiovascular autonomic nervous system. Nat Rev Cardiol. 23, pages 255–278. doi.org/10.1038/s41569-025-01212-4
Li N, Zhang C, Xu M Choi Y, Sidarta-Oliveira D, Dong R, Hu X, Toledo EM, Prada-Medina CA, Argus F, Liu K, Li M, Zhou L, Bayley H, Smith C, Denning C, Domingos AI, Hao G, Li D, Paterson DJ (2026). Human-derived cardiac-neural microtissues reveal catecholaminergic polymorphic ventricular tachycardia is also a disease of the sympathetic neuron. J Physiol (15February). doi.org/10.1113/JP290024
