DOCnet Project
Published August 1, 2018 | Version v1
Journal article Open

Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

Creators

  • 1. Department of Cardiology, CUB Hoˆpital Erasme, Universite´ Libre de Bruxelles, Brussels, Belgium
  • 2. Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy
  • 3. Department of Translational Medical Sciences, Federico II University, Naples, Italy
  • 4. Department of Cardiology, Maastricht University Medical Center & CARIM, Maastricht University, Maastricht, The Netherlands
  • 5. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK
  • 6. School of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
  • 7. Department of Systems Physiology, Ruhr University Bochum, Bochum, Germany
  • 8. Molecular Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
  • 9. Department of Cardiology, Heidelberg University, Heidelberg, Germany
  • 10. Cardiovascular R&D Unit, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal;
  • 11. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
  • 12. Department of Physiology, VU University Medical Centre, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
  • 13. Cardiovascular Research Center, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK

Description

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance—malignancy of the mutated gene—but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.

Notes

The authors acknowledge the support from the Netherlands Cardiovascular Research Initiative, with support of the Dutch Heart Foundation, CVON2011-ARENA, CVON2018-ARENA PRIME, CVON2016-Early HFPEF, and CVON 2017-ShePREDICTS to S.H. S.H. received funding from the European Union Commission's Seventh Framework programme under grant agreement N 305507 (HOMAGE), N 602904 (FIBROTARGETS), and FP7-Health-2013- Innovations-1 N 602156 (HECATOS). E.A. received support from the EU funded project INHERITANCE (n241924), from the Italian Ministry of Health, from the Cariplo Foundation, and from the Magica Onlus Charity. A.B. received support from the Erasme Foundation (ULB) and from the Belgian Cardiac Surgery Foundation. M.C. from the Funds for Basic Research-University of Salerno (FARB2016-2017). A.L. was supported by the Project DOCnet (NORTE-01-0145-FEDER-000003), by the Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by the project NETDIAMOND (POCI-01-0145-FEDER-016385), supported by European Structural and Investment Funds, Lisbon's Regional Operational Program 2020 and Portuguese funds from the Portuguese Foundation for Science and Technology. B.M. received funding from European Union (FP7 INHERITANCE, BestAgeing, ERA-CVD DetectinHF), from the Klaus Tschira Foundation, and from CaRNAtion. C.G.T. was supported by a Federico II University grant 'Ricerca di Ateneo'. J.V.D.V. received a grant from the Dutch Heart Foundation (CVONDosis 2014-40). N.H. was supported by a Deutsche Forshungsgemeinschaft (DFG) grant (HA 7512/2-1). R.W. was supported by the National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit based at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, the Wellcome Trust (107469/Z/15/Z) and the British Heart Foundation (SP/10/10/28431). T.T. received funding from European Union, ERANET (Expert) and the ERC Consolidator grant Longheart. E.U. funded project INHERITANCE (n241924) and the Italian Ministry of Health Grants to E.A.

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