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  • Review Article
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Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target

Abstract

Ca2+ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca2+ ([Ca2+]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca2+-binding proteins. Defective regulation of [Ca2+] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca2+] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca2+-release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca2+ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca2+ leak as a shared Ca2+-dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca2+ leak from the SR, are undergoing investigation in clinical trials.

Key points

  • Cardiac ryanodine receptor 2 (RYR2) Ca2+-release channels are required for excitation–contraction coupling in the heart.

  • Pathological oxidation and PKA-mediated hyperphosphorylation of RYR2 or inherited RYR2 mutations can cause RYR2 Ca2+ leak from the sarcoplasmic reticulum during diastole, contributing to the progression of heart failure.

  • Diastolic Ca2+ leak from RYR2 in atrial and ventricular myocytes can also lead to atrial and ventricular arrhythmias, respectively.

  • Inhibiting this Ca2+ leak with the use of drugs that stabilize the interactions between calstabin 2 and RYR2 can reduce the progression of heart failure and the incidence of cardiac arrhythmias such as atrial fibrillation.

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Fig. 1: Diastolic Ca2+ leak from the SR via RYR2 in ventricular myocytes from failing hearts.
Fig. 2: Reduced Ca2+ transient amplitudes in ventricular myocytes from failing hearts.
Fig. 3: Diastolic Ca2+ leak from the SR via RYR2 triggers AF in atrial myocytes.
Fig. 4: Architecture of the closed and open states of RYR2.
Fig. 5: RYR2 phosphorylation domain and mutation hot spots associated with CPVT and ARVC.
Fig. 6: Contact sites between neighbouring RYR2 channels might promote coupled gating.

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Acknowledgements

The authors are supported by NIH grants R01HL145473, R01DK118240, R01HL142903, R01HL140934, R01AR070194 and T32 HL120826 (to A.R.M.). The authors thank the current and former members of the Marks laboratory for their contributions to the research discussed in this Review.

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R.Z. and A.R.M. researched data for the article. All the authors contributed to writing the manuscript, and A.R.M. reviewed and edited the manuscript before submission.

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Correspondence to Andrew R. Marks.

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A.R.M. and Columbia University, USA, own shares in ARMGO Pharma, a biotechnology company developing ryanodine receptor-targeted drugs.

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Dridi, H., Kushnir, A., Zalk, R. et al. Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Nat Rev Cardiol 17, 732–747 (2020). https://doi.org/10.1038/s41569-020-0394-8

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