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Lamin and the heart
  1. Gabriella Captur1,2,3,
  2. Eloisa Arbustini4,
  3. Gisèle Bonne5,
  4. Petros Syrris6,
  5. Kevin Mills1,7,
  6. Karim Wahbi5,8,9,
  7. Saidi A Mohiddin10,
  8. William J McKenna6,
  9. Stephen Pettit11,
  10. Carolyn Y Ho12,
  11. Antoine Muchir5,
  12. Paul Gissen7,13,14,
  13. Perry M Elliott2,3,6,
  14. James C Moon2,3,6
  1. 1 UCL Biological Mass Spectrometry Laboratory, Institute of Child Health and Great Ormond Street Hospital, London, UK
  2. 2 Biomedical Research Center, NIHR University College London Hospitals, London, UK
  3. 3 The Cardiovascular Magnetic Resonance Imaging Unit and The Inherited Cardiovascular Diseases Unit, Barts Heart Center, St Bartholomew’s Hospital, London, UK
  4. 4 Center for Inherited Cardiovascular Diseases, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
  5. 5 INSERMUMRS974, CNRS FRE3617, Centre de Recherche en Myologie, Sorbonne Universités, UPMC Univ Paris 06, Institutde Myologie, Paris, France
  6. 6 Institute of Cardiovascular Science, University College London, London, UK
  7. 7 Institute of Child Health, University College London, London, UK
  8. 8 Sorbonne Paris Cité, Université Paris Descartes, Paris, France
  9. 9 Service de Cardiologie, AP-HP Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Paris, France
  10. 10 NIHR Cardiovascular Biomedical Research Unit at Barts, Barts Heart Center, William Harvey Research Institute, Queen Mary University of London, London, UK
  11. 11 Transplant Unit, Papworth Hospital NHS Foundation Trust, Cambridge, UK
  12. 12 Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
  13. 13 MRC Laboratory for Molecular Cell Biology, University College London, London, UK
  14. 14 Inherited Metabolic Diseases Unit, Great Ormond Street Hospital, London, UK
  1. Correspondence to Professor James C Moon, Barts Heart Center, Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK; j.moon{at}ucl.ac.uk

Abstract

Lamins A and C are intermediate filament nuclear envelope proteins encoded by the LMNA gene. Mutations in LMNA cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an LMNA mutation may be quite high.

Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for LMNA, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.

Genotyping and family screening are clinically important both to confirm and to exclude LMNA mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our LMNA knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

  • cardiac imaging and diagnostics
  • advanced cardiac imaging
  • cardiac magnetic resonance (cmr) imaging
  • heart transplantation
  • implanted cardiac defibrillators

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Footnotes

  • Contributors GC conducted the literature search, wrote the manuscript and made the figures and tables. JCM planned and wrote the manuscript and provided expert review of the manuscript. EA made a figure and provided expert review of the manuscript. PS conducted a literature search, reviewed a table and provided expert review of the manuscript. SP, GB, AM, KM,KW, SM, WJM, CH, PG and PME provided expert review of the manuscript.

  • Funding GC and JCM are supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC, #171603), by the Society for Cardiovascular Magnetic Resonance (SCMR Seed Grant #2017) and by University College London Hospitals NIHR Biomedical Research Center. JCM is indirectly supported by the Biomedical Research Unit at Barts Hospital. PS is funded by the University College London Hospitals NIHR Biomedical Research Center, and his research is supported by the Fondation Leducq. AM, KW and GB are supported by the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie-Paris 6, the Centre National de la Recherche Scientifique and the Association Française contre les Myopathies.

  • Competing interests AM is a member of the scientific advisory board of AlloMek Therapeutics, LLC, a privately held pharmaceutical company developing small molecules targeting ERK1/2 signalling. All other authors have declared no conflicts of interest.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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