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Mechanisms of ryanodine receptor 2 dysfunction in heart failure

Nature Reviews Cardiology volume 17, page 748 (2020)Cite this article

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In the Review by Dridi and colleagues (Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0394-8 (2020))1, the authors discuss the role of Ca2+ leak via cardiac ryanodine receptor 2 (RYR2) as a shared pathological mechanism in heart failure and atrial fibrillation. We agree with the authors’ overall conclusion that Ca2+ leak from the sarcoplasmic reticulum is a key trigger of cardiac arrhythmia but disagree with their interpretation of the underlying mechanisms.

The authors propose a simplified mechanism, in which cAMP-dependent protein kinase (PKA)-mediated phosphorylation of RYR2 at Ser2808 is increased in heart failure and atrial fibrillation, ‘hyperphosphorylation’ of Ser2808 dissociates the FK506-binding protein 12.6 (FKBP12.6) subunit (called ‘calstabin 2’ almost exclusively by the authors), FKBP12.6-dissociated RYR2 becomes dysfunctional, and RYR2-mediated Ca2+ leak promotes arrhythmia and impairs contractility1. This mechanism has been advanced by the authors not only in heart failure but also in inherited arrhythmias, muscular dystrophy, seizures, cognitive dysfunction and diabetes mellitus (reviewed previously2).

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References

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Acknowledgements

The authors are supported by grants from the AHA (19CDA34660208 to F.J.A.) and the NIH (HL055438 and HL134344 to H.H.V.).

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  1. Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison, Madison, WI, USA

    Francisco J. Alvarado & Héctor H. Valdivia

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  1. Francisco J. Alvarado
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  2. Héctor H. Valdivia
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Correspondence to Francisco J. Alvarado or Héctor H. Valdivia.

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Alvarado, F.J., Valdivia, H.H. Mechanisms of ryanodine receptor 2 dysfunction in heart failure. Nat Rev Cardiol 17, 748 (2020). https://doi.org/10.1038/s41569-020-00443-x

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