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  • Review Article
  • Published:

Cardiac optogenetics: a decade of enlightenment

Nature Reviews Cardiology volume 18, pages 349–367 (2021)Cite this article

Subjects

Abstract

The electromechanical function of the heart involves complex, coordinated activity over time and space. Life-threatening cardiac arrhythmias arise from asynchrony in these space–time events; therefore, therapies for prevention and treatment require fundamental understanding and the ability to visualize, perturb and control cardiac activity. Optogenetics combines optical and molecular biology (genetic) approaches for light-enabled sensing and actuation of electrical activity with unprecedented spatiotemporal resolution and parallelism. The year 2020 marks a decade of developments in cardiac optogenetics since this technology was adopted from neuroscience and applied to the heart. In this Review, we appraise a decade of advances that define near-term (immediate) translation based on all-optical electrophysiology, including high-throughput screening, cardiotoxicity testing and personalized medicine assays, and long-term (aspirational) prospects for clinical translation of cardiac optogenetics, including new optical therapies for rhythm control. The main translational opportunities and challenges for optogenetics to be fully embraced in cardiology are also discussed.

Key points

  • Cardiac optogenetics leverages genetically encoded optical sensors and actuators to empower basic and translational research, as evidenced by an impressive growth of published reports over the past decade.

  • Immediate translational opportunities reside in all-optical platforms that are inherently high-throughput, offering rapid testing and discovery of new drugs and therapies with the use of patient-derived cells for personalized medicine and myocardial regeneration.

  • Optogenetics offers technical innovations for cardiac rhythm control in patients and long-term opportunities for clinical translation for ultra-low-energy rhythm control, precise autonomic neuromodulation and painless defibrillation, which are based on the cell-specificity and space–time resolution of optogenetics.

  • Challenges in translating cardiac optogenetics to the clinic are mainly linked to safe opsin delivery to the heart, cell-specific expression and engaging the opsins with light deep within the tissue.

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Fig. 1: Timeline of optical tools applied to the heart.
Fig. 2: Advantages of all-optical electrophysiology and the optogenetic toolkit.
Fig. 3: Near-term translation for high-throughput drug screening and cardiotoxicity testing.
Fig. 4: Near-term translation to enhance stem cell technology and personalized medicine.
Fig. 5: Long-term translation of cardiac optogenetics for rhythm control.
Fig. 6: Long-term translation of cardiac optogenetics for wave control and feedback control.
Fig. 7: Long-term translation of cardiac optogenetics for cell-specific control.

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Acknowledgements

In this Review, we have attempted a comprehensive coverage of all work in the area over the past 10 years; we apologize for any potentially missing publications. We greatly appreciate the critical contributions of scientists and trainees in the Entcheva laboratory and of the Kay laboratory at The George Washington University, USA, for their many questions and discussions regarding numerous scientific aspects of cardiac optogenetics. For the figures in the initial submission of the manuscript, former trainees A. Klimas prepared a draft of parts of Fig. 2 and Y. Wu prepared parts of Fig. 4 (disease modelling), and current trainee B. Alber prepared parts of Fig. 7. The authors are supported in part by grants from the NIH (R01-HL144157, R01-HL133862, R01-HL146169, R01-HL147279 and R21-EB026152) and the National Science Foundation (EFMA 1830941, CBET1705645 and PFI 1827535).

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    Emilia Entcheva & Matthew W. Kay

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Both the 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.

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Glossary

Tandem cell unit

A multicellular unit composed of light-sensitive, non-excitable cells that are electrically coupled to non-transduced excitable cells.

Optical dynamic clamp

A real-time feedback system to ‘inject’ a desired current into light-sensitized cells or tissue according to a computer model and voltage measurements.

Cardioversion

A procedure that restores normal sinus rhythm to a heart that has an arrhythmia.

Gene painting

Transduction of tissue with a gene by ‘painting’ it with adenovirus, using a solution containing the vector, an adhering polymer and a weak protease to promote vector penetration.

Up-conversion nanoparticles

Optical nanomaterials, typically doped with lanthanide ions, that up-convert two or more lower energy photons (longer wavelengths) into one high-energy photon (shorter wavelength).

Optical wave steering

A procedure in which specific space–time dynamic light patterns are used to control the speed and direction of an electrical wavefront within excitable tissue that expresses an opsin.

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Entcheva, E., Kay, M.W. Cardiac optogenetics: a decade of enlightenment. Nat Rev Cardiol 18, 349–367 (2021). https://doi.org/10.1038/s41569-020-00478-0

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