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InsP3R–RyR Ca2+ channel crosstalk facilitates arrhythmias in the failing human ventricle

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Abstract

Dysregulated intracellular Ca2+ handling involving altered Ca2+ release from intracellular stores via RyR channels underlies both arrhythmias and reduced function in heart failure (HF). Mechanisms linking RyR dysregulation and disease are not fully established. Studies in animals support a role for InsP3 receptor Ca2+ channels (InsP3R) in pathological alterations in cardiomyocyte Ca2+ handling but whether these findings translate to the divergent physiology of human cardiomyocytes during heart failure is not determined. Using electrophysiological and Ca2+ recordings in human ventricular cardiomyocytes, we uncovered that Ca2+ release via InsP3Rs facilitated Ca2+ release from RyR and induced arrhythmogenic delayed after depolarisations and action potentials. InsP3R–RyR crosstalk was particularly increased in HF at RyR clusters isolated from the T-tubular network. Reduced SERCA activity in HF further facilitated the action of InsP3. Nanoscale imaging revealed co-localisation of InsP3Rs with RyRs in the dyad, which was increased in HF, providing a mechanism for augmented Ca2+ channel crosstalk. Notably, arrhythmogenic activity dependent on InsP3Rs was increased in tissue wedges from failing hearts perfused with AngII to promote InsP3 generation. These data indicate a central role for InsP3R–RyR Ca2+ signalling crosstalk in the pro-arrhythmic action of GPCR agonists elevated in HF and the potential for their therapeutic targeting.

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Acknowledgements

This work was supported by the Fund for Scientific Research-Flanders and KULeuven. Specifically, FWO projects G.0918.15 to KRS, G0C7319N to KRS and FR, FWO Project grant G08861N and FWO Odysseus Project 90663 to HLR, FWO postdoctoral fellowships to ED and GG and FWO PhD fellowship to MA. We also acknowledge support from the FWO for the STED Abberior microscope (Cell & tissue Imaging Cluster, CIC) (FWO Hercules funding I001918N to PVB, HLR et al.). We thank Annemie Biesmans for technical assistance, the transplant team of UZ Leuven for help in providing human explanted hearts, and Prof J Van Cleemput, head of the HF clinic for support in the research program. This work was supported by Fonds Wetenschappelijk Onderzoek (G.0617.09).

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Author notes

  1. Xin Jin

    Present address: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

  2. Matthew Amoni and Guillaume Gilbert have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Sciences, Laboratory of Experimental Cardiology, KU Leuven, 3000, Leuven, Belgium

    Xin Jin, Matthew Amoni, Guillaume Gilbert, Eef Dries, Rosa Doñate Puertas, Ashutosh Tomar, Chandan K. Nagaraju, Ankit Pradhan, Roxane Menten, Filip Rega, Karin Sipido & H. Llewelyn Roderick

  2. Department of Pharmacology and Physiology, Medical Center School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 711, Rochester, NY, 14642, USA

    David I. Yule

  3. Laboratory for Enteric NeuroScience (LENS), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, 3000, Leuven, Belgium

    Tobie Martens & Pieter Vanden Berghe

  4. Cell and Tissue Imaging Cluster (CIC), KU Leuven, 3000, Leuven, Belgium

    Tobie Martens & Pieter Vanden Berghe

  5. Department of Cardiology and Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium

    Filip Rega

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Contributions

Conceptualisation: HLR; Funding acquisition: HLR, KS; Study design: HLR, XJ, KS; Conducting experiments: XJ, RM, MA, GG, RD; Acquiring data: XJ, RM, MA, GG, RD; Analysing data: XJ, RM, MA, GG, HLR, TM, PVB, RD, AT; Providing reagents: DY, FR, CN; Writing the manuscript: XJ, HLR, KS; Writing review and editing: all authors.

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Correspondence to H. Llewelyn Roderick.

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Conflict of interest

Dr. Rega has received research funding from Medtronic; and has been a consultant to AtriCure and LivaNova. All other authors declare no conflicts of interest.

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Jin, X., Amoni, M., Gilbert, G. et al. InsP3R–RyR Ca2+ channel crosstalk facilitates arrhythmias in the failing human ventricle. Basic Res Cardiol 117, 60 (2022). https://doi.org/10.1007/s00395-022-00967-y

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  • DOI: https://doi.org/10.1007/s00395-022-00967-y

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