Abstract
The cardiac conduction system (CCS) has a vital role in initiating and coordinating nearly 3 billion heartbeats throughout a person’s lifetime. The CCS comprises two primary tissue types: the impulse-generating, slow-conducting nodes and the fast-conducting components of the ventricular conduction system. Dysfunction in this system can give rise to a spectrum of clinical symptoms, including palpitations, syncope, heart failure and even sudden cardiac death. Owing to the limited therapeutic options other than electronic pacemakers, substantial research efforts have been aimed at uncovering the root causes of conduction system disorders. A comprehensive investigative approach integrating genetics, transcriptomics and proteomics has been used to unravel the complex biology of these diseases. Advances in single-cell genomic and transcriptomic technologies, together with spatial transcriptomics, are offering new insights into the cellular microenvironments that govern conduction system function. In this Review, we examine the latest progress in understanding the biology of the CCS, situating new findings within both established and emerging scientific paradigms. Additionally, we discuss how these insights can be leveraged to improve clinical risk assessment, expand drug discovery efforts, accelerate technology aimed at promoting CCS regeneration and foster the development of innovative therapies, including biological pacemakers.
Key points
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The cardiac conduction system (CCS) initiates each heartbeat and regulates the flow of electrical impulses throughout the heart.
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Diseases of the CCS are a major cause of morbidity and mortality worldwide; research into therapeutic alternatives to electronic pacemakers is driving new discoveries in CCS biology.
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CCS-restricted gene regulatory networks reinforce specialized conduction phenotypes and simultaneously repress working cardiomyocyte-specific programming.
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Transcriptomic analyses at single-cell resolution, combined with spatial transcriptomics, are offering unprecedented insights into the local tissue microenvironments of the CCS and are driving advances in next-generation tools for drug discovery and therapies specifically targeting the conduction system.
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Development of biological pacemakers that use transcription factors to reprogramme working cardiomyocytes into CCS cells holds substantial therapeutic potential.
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Acknowledgements
D.S.P. receives research funding from the National Institutes of Health (R01HL165130 and R01HL171989). G.I.F. receives research funding from the National Institutes of Health (R01 HL171118 and R01HL159869). The authors thank N. Yamaguchi (NYU Grossman School of Medicine, USA) for assistance with the generation of tables and figures for initial submission.
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Park, D.S., Fishman, G.I. The cardiac conduction system: development, function and therapeutic targets. Nat Rev Cardiol (2026). https://doi.org/10.1038/s41569-025-01227-x
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DOI: https://doi.org/10.1038/s41569-025-01227-x
