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Next-generation pacemakers: from small devices to biological pacemakers

Key Points

  • The heartbeat originates from spontaneous depolarizations in the sinoatrial node, which lead to the spread of electrical signals throughout the heart via a specialized conduction system

  • Failure of the sinoatrial node pacemaker or disease of the conduction system results in slow heart rates that can cause fainting or sudden death

  • Current therapies rely on electronic pacemakers to provide an adequate heart rate to satisfy haemodynamic needs

  • Electronic pacemaker technologies continue to evolve; however, electronic pacemakers have limitations including battery life, system failure, inability to provide true autonomic response, and device-related infections

  • Biological pacemakers, currently at the preclinical stage, might be an alternative to electronic devices for selected patients in the future

Abstract

Electrogenesis in the heart begins in the sinoatrial node and proceeds down the conduction system to originate the heartbeat. Conduction system disorders lead to slow heart rates that are insufficient to support the circulation, necessitating implantation of electronic pacemakers. The typical electronic pacemaker consists of a subcutaneous generator and battery module attached to one or more endocardial leads. New leadless pacemakers can be implanted directly into the right ventricular apex, providing single-chamber pacing without a subcutaneous generator. Modern pacemakers are generally reliable, and their programmability provides options for different pacing modes tailored to specific clinical needs. Advances in device technology will probably include alternative energy sources and dual-chamber leadless pacing in the not-too-distant future. Although effective, current electronic devices have limitations related to lead or generator malfunction, lack of autonomic responsiveness, undesirable interactions with strong magnetic fields, and device-related infections. Biological pacemakers, generated by somatic gene transfer, cell fusion, or cell transplantation, provide an alternative to electronic devices. Somatic reprogramming strategies, which involve transfer of genes encoding transcription factors to transform working myocardium into a surrogate sinoatrial node, are furthest along in the translational pipeline. Even as electronic pacemakers become smaller and less invasive, biological pacemakers might expand the therapeutic armamentarium for conduction system disorders.

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Figure 1: Cardiac conduction system.
Figure 2: Mechanisms of sinoatrial node automaticity.
Figure 3: Timeline of the evolution of electronic pacemakers.
Figure 4: Biological pacemaker approaches.
Figure 5: Somatic reprogramming by TBX18.

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Acknowledgements

The authors' work on biological pacemakers in funded by the US NIH RO1 HL135866 and NIH RO1 HL048509.

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Authors and Affiliations

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article, and undertook review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Eduardo Marbán.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

Action potential

A rise and fall in the electrical potential of the surface membrane of the cell produced by the flow of ions across the cell membrane; pacemaker cells generate spontaneous action potentials that in turn can elicit action potentials in neighbouring cells.

Diastolic depolarization

The spontaneous depolarization of the resting membrane potential during diastole; a unique property of pacemaker cardiomyocytes.

Asynchronous pacing

Fixed rate pacing delivered by the implanted pacemaker independent of any atrial or ventricular activity.

Synchronous pacing

Pacing delivered from the implanted pacemaker on demand if no atrial or ventricular activity is sensed.

Sick sinus syndrome

A sinoatrial node disease that results in slow heart rhythms.

Optical mapping

A laboratory technique that allows high-resolution mapping of the electrical activity of the heart.

Syngeneic

Genetically similar or identical, and hence immunologically compatible.

Heterokaryons

Multinucleate cells that contain genetically different nuclei.

Electroanatomical mapping

A technique used both in the clinic and experimentally that allows mapping of the electrical activity of the heart in vivo.

AV synchrony

The sequential contraction of the atria and the ventricles.

Hydrops fetalis

A serious fetal condition defined as abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin oedema.

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Cingolani, E., Goldhaber, J. & Marbán, E. Next-generation pacemakers: from small devices to biological pacemakers. Nat Rev Cardiol 15, 139–150 (2018). https://doi.org/10.1038/nrcardio.2017.165

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