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  • Review Article
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Cardiac splicing as a diagnostic and therapeutic target

Nature Reviews Cardiology volume 20, pages 517–530 (2023)Cite this article

Subjects

Abstract

Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing — including the identification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials — provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.

Key points

  • Human genetic variation associated with severe forms of cardiomyopathy and arrhythmia has highlighted the crucial role of alternative splicing in myocardial health and disease.

  • Alternative splicing governs major adaptations in cardiac physiology and pathology, including the re-expression of fetal and perinatal isoforms in heart failure.

  • Up to 10% of mutations in cardiac disease-related genes affect splice sites.

  • Splicing factor mutations alter the global protein composition of cardiomyocytes, resulting in complex disease phenotypes.

  • Technical advances have enabled the global analysis of cardiac isoform expression through multiomics and single-cell approaches, with implications for improved clinical decision-making and patient care.

  • Cardiac splice regulators can be targeted therapeutically through small-molecule and antisense oligonucleotide approaches, whereas splice site mutations are now accessible to gene editing and trans-splicing.

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Fig. 1: Alternative splicing.
Fig. 2: Genotype and phenotype relationships in cardiac splicing disease.
Fig. 3: Analysis of splice networks.
Fig. 4: Splice diagnostics by mRNA sequencing of distinct splice defects.
Fig. 5: Translating basic research into improved splice therapeutics and clinical care.

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Acknowledgements

This work was funded by Leducq TAN CASTT grant 21CVD02. Jacobo Lopez Carballo (Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany) supported the data analysis and generation of the supplementary tables.

Author information

Authors and Affiliations

  1. Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Michael Gotthardt & Victor Badillo-Lisakowski

  2. DZHK (German Center for Cardiovascular Research Partner Site Berlin), Berlin, Germany

    Michael Gotthardt & Victor Badillo-Lisakowski

  3. Department of Cardiology, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Michael Gotthardt

  4. Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Palo Alto, CA, USA

    Victoria Nicole Parikh & Euan Ashley

  5. Stanford Genome Technology Center, Stanford University, Palo Alto, CA, USA

    Euan Ashley & Lars Steinmetz

  6. Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA

    Euan Ashley & Lars Steinmetz

  7. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Marta Furtado & Maria Carmo-Fonseca

  8. Institute for Cardiomyopathies, Department of Medicine III, University of Heidelberg, Heidelberg, Germany

    Sarah Schudy & Benjamin Meder

  9. DZHK (German Center for Cardiovascular Research Partner Site Heidelberg-Mannheim), Heidelberg, Germany

    Benjamin Meder

  10. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany

    Markus Grosch & Lars Steinmetz

  11. Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO, USA

    Claudia Crocini & Leslie Leinwand

Authors
  1. Michael Gotthardt
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  2. Victor Badillo-Lisakowski
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  3. Victoria Nicole Parikh
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  4. Euan Ashley
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  5. Marta Furtado
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  6. Maria Carmo-Fonseca
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  7. Sarah Schudy
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  8. Benjamin Meder
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  9. Markus Grosch
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  10. Lars Steinmetz
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  11. Claudia Crocini
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  12. Leslie Leinwand
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Contributions

M. Gotthardt, V.B.-L., V.N.P., M.F., S.S., M. Grosch, C.C. and L.L. researched data for the article. M. Gotthardt, V.B.-L., V.N.P., E.A., M.C.-F., B.M., M. Grosch, L.S. and L.L. discussed the content of the article. All the authors wrote the manuscript. M. Gotthardt and L.L. reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Michael Gotthardt.

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Competing interests

M. Gotthardt has a consultancy agreement with River BioMedics and has received speaker honoraria from Bayer. V.N.P. reports a sponsored research agreement with BioMarin and consulting relationships with Constantiam and viz.ai. E.A. reports sponsored research from Bristol Myers Squibb, has ownership interest in DeepCell, Nuevocor and Personalis, and is a board member of AstraZeneca. M.C.-F. is a cofounder and scientific adviser of GenoMed, a molecular diagnosis company. B.M. holds stocks in biotech and pharma, has received speaker honoraria from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Novartis and Pfizer, and is on the Scientific Advisory Boards of Bristol Myers Squibb/Myokardia and Fleischhacker. L.S. is a co-founder of SOPHiA Genetics, as well as co-founder and board member of LevitasBio and Recombia Biosciences, and receives research support from GlaxoSmithKline. L.L. has sponsored research agreements from Bristol Myers Squibb and Edgewise Therapeutics, and is on the scientific advisory boards of Bristol Meyers Squibb/MyoKardia and Edgewise Therapeutics. The other authors declare no competing interests.

Peer review

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Nature Reviews Cardiology thanks Samuel Dudley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Alamut software: https://www.sophiagenetics.com/platform/alamut-visual-plus/

AltAnalyze: http://www.altanalyze.org/

ClinVar database: https://www.ncbi.nlm.nih.gov/clinvar/

Cytoscape: https://cytoscape.org/

Gene Ontology: https://www.ebi.ac.uk/QuickGO/

GTEx: https://gtexportal.org/home/

Human Protein Atlas: https://www.proteinatlas.org/

Oxford Nanopore Technology: https://nanoporetech.com

Pacific Biosciences: https://www.pacb.com

VALERIE: https://cran.r-project.org/package=VALERIE

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Gotthardt, M., Badillo-Lisakowski, V., Parikh, V.N. et al. Cardiac splicing as a diagnostic and therapeutic target. Nat Rev Cardiol 20, 517–530 (2023). https://doi.org/10.1038/s41569-022-00828-0

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