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  • Review Article
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Multimodal, device-based therapeutic targeting of the cardiovascular autonomic nervous system

Nature Reviews Cardiology (2025)Cite this article

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Abstract

The miniaturization of implantable sensors and actuators, combined with advances in interactive modelling and high-resolution imaging, is propelling the use of medical devices for counteracting impaired neural control of the cardiovascular system. In this Review, we discuss the current effectiveness of this technology for modulating autonomic activity in numerous cardiovascular conditions, including high blood pressure, heart failure and cardiac arrhythmias. We advocate for smarter closed-loop bionic devices fitted with feedback from multiple sensors to allow adaptive, state-dependent control, and discuss how the adoption of artificial intelligence technology would facilitate auto-personalization to meet the needs of patients. We also describe how transcriptomics of autonomic circuits can guide device-based approaches. Finally, the use of stem cell therapies to target sympathetic circuits more precisely will help to optimize the therapeutic effects of autonomic modulation for the treatment of arrhythmia. For bioelectronic medicine to achieve clinical utility in neurocardiology, these innovations must demonstrate improved efficacy beyond that offered by contemporary interventions.

Key points

  • Emerging evidence suggests that bioelectronic strategies that involve the site-specific targeting of the autonomic circuit could be used to treat cardiovascular diseases, including arrhythmia, heart failure and neurogenic hypertension.

  • Advances in implantable sensor technology and device miniaturization, together with the design of closed-loop bioelectronics linked to multi-feedback sensors, should contribute to the development of therapies to modulate autonomic nervous system activity.

  • Combining artificial intelligence and machine learning technologies with novel neuroceutical devices could result in optimized and personalized parameter set points that respond to physiological feedback within a closed-loop system, thereby enabling dynamic state-dependent adjustment.

  • Advances in Bluetooth technology might facilitate real-time device readout, effectiveness and feedback dosing of neuroceutical devices.

  • The use of transcriptomics to understand whether visceral reflex pathways are associated with distinct phenotypes might enable highly selective functional neuromodulation in device-based medicine.

  • The autografting of novel biomaterials into the autonomic nervous system or to the end organ, such as the heart, to alter excitability with closed-loop bioelectronics is promising for the treatment of arrhythmias.

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Fig. 1: Integrative sensory neural control of the blood circulation mediated by the autonomic nervous system.
Fig. 2: Autonomic dysregulation and pathological phenotypes in heart failure.
Fig. 3: Proposed configurations of neuroceutical device actuators with incorporated sensory feedback and AI–ML technologies for treating cardiac diseases.
Fig. 4: Making neuroceuticals more physiological with closed-loop feedback.
Fig. 5: Phenotypically distinct afferents from carotid body driving the sympathetic nervous system.
Fig. 6: High-resolution and high-fidelity computational model of closed-loop control of cardiac physiology incorporating molecular, anatomical and connectome details of the central and peripheral autonomic nervous circuits.
Fig. 7: Global data repository of autonomic nervous system data for high resolution mapping on common cardiovascular scaffolds.
Fig. 8: Novel targeting of multifunctional cardiac sympathetic neurons in inherited cardiac arrhythmias.
Fig. 9: Future interventional approaches and targets for restoring autonomic imbalance in cardiovascular disease.

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Acknowledgements

J.F.R.P. is funded by the Health Research Council, Marsden Fund, the Royal Society of New Zealand, the Sidney Taylor Trust and is an inaugural Partridge Family laureate. J.F.R.P. was supported by a visiting research fellowship at Merton College, Oxford, during the writing of this Review with D.J.P. R.V. is funded by the National Heart Lung and Blood Institute (R01 HL161696). N.H. is supported by a British Heart Foundation Senior Clinical Research Fellowship (FS/SCRF/20/32005). D.J.P. is supported by a BHF Special Project Grant (SP/F/22/150027) and a Leducq International Network of Excellence Award (23CVD04) on Bioelectronics for Neurocardiology (with N.H.).

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Authors and Affiliations

  1. Manaaki Manawa — The Centre of Heart Research, Faculty of Medical & Health Sciences, University of Auckland, Grafton Campus, Auckland, New Zealand

    Julian F. R. Paton

  2. Department of Experimental and Clinical Physiology, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland

    Tymoteusz Żera

  3. Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    Rajanikanth Vadigepalli

  4. Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK

    Neil Herring & David J. Paterson

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J.F.R.P., T.Z., N.H. and D.J.P. researched data and wrote the article. J.F.R.P., N.H. and D.J.P. contributed to the discussion of its content. All authors reviewed and edited the manuscript before submission.

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Paton, J.F.R., Żera, T., Vadigepalli, R. et al. Multimodal, device-based therapeutic targeting of the cardiovascular autonomic nervous system. Nat Rev Cardiol (2025). https://doi.org/10.1038/s41569-025-01212-4

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