[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Genetic Testing as a Guide for Treatment in Dilated Cardiomyopathies

  • Myocardial Disease (A Abbate and M Merlo, Section Editors)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Dilated cardiomyopathy (DCM) is one of the most prevalent primary cardiomyopathies and may be caused by genetic and non-genetic etiologies. DCM may also be the final common pathway of other cardiomyopathies such as hypertrophic, arrhythmogenic, or non-compaction cardiomyopathy. We review the main DCM genetic substrates, specific genotype–phenotype aspects, the role of genetic testing in risk stratification, and advances regarding genotype-based precision medicine.

Recent Findings

Performing a comprehensive genetic study could have a diagnostic yield up to 40% in DCM, and it is considered a cost-effective approach nowadays. The detection of a specific underlying genetic substrate explaining the disease can have important consequences for clinical management, especially for familial cascade screening, optimizing medical treatment, and improving the arrhythmic risk stratification.

Summary

The identification of the genetic substrate underlying dilated cardiomyopathy makes possible the genotype-phenotype correlation analysis and a better understanding of the natural history of this disease. Nowadays, there are many promising targeting-gene therapies in different developing phases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Böhm M, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37(23):1850–8.

    Article  Google Scholar 

  2. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Vol. 42, European Heart Journal. Oxford University Press. 2021:3599–726.

  3. Hazebroek MR, Krapels I, Verdonschot J, van den Wijngaard A, Vanhoutte E, Hoos M, et al. Prevalence of pathogenic gene mutations and prognosis do not differ in isolated left ventricular dysfunction compared with dilated cardiomyopathy. Circ Heart Fail. 2018;11(3): e004682.

    Article  CAS  Google Scholar 

  4. Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16(11):e301–72.

    Article  Google Scholar 

  5. Hänselmann A, Veltmann C, Bauersachs J, Berliner D. Dilated cardiomyopathies and non-compaction cardiomyopathy. Vol. 45, Herz. Springer Medizin. 2020:212–20.

  6. McKenna WJ, Judge DP. Epidemiology of the inherited cardiomyopathies. Vol. 18, Nature Reviews Cardiology. Nature Res. 2021:22–36.

  7. Schultheiss HP, Fairweather DL, Caforio ALP, Escher F, Hershberger RE, Lipshultz SE, et al. Dilated cardiomyopathy. Nature Rev Dis Prim. 2019;5(1).

  8. Seidelmann SB, Laur O, Hwa J, Depasquale E, Bellumkonda L, Sugeng L, et al. Familial dilated cardiomyopathy diagnosis is commonly overlooked at the time of transplant listing. J Heart Lung Transplant. 2016;35(4):474–80.

    Article  Google Scholar 

  9. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014;16(8):601–8.

    Article  CAS  Google Scholar 

  10. Verdonschot JAJ, Hazebroek MR, Krapels IPC, Henkens MTHM, Raafs A, Wang P, et al. Implications of genetic testing in dilated cardiomyopathy. Circulat: Gen Precis Med. 2020;476–87.

  11. Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. EP Europace [Internet]. 2022. Available from: https://academic.oup.com/europace/advance-article/doi/10.1093/europace/euac030/6562982.

  12. Mogensen J, van Tintelen JP, Fokstuen S, Elliott P, van Langen IM, Meder B, et al. The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics. Europ Heart J. Oxford University Press; 2015;36:1367–70.

  13. Herman DS, Lam L, Taylor MRG, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619–28.

    Article  CAS  Google Scholar 

  14. Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JDH, Lekanne Deprez RH, et al. Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy. Eur J Heart Fail. 2017;19(4):512–21.

    Article  CAS  Google Scholar 

  15. Corden B, Jarman J, Whiffin N, Tayal U, Buchan R, Sehmi J, et al. Association of titin-truncating genetic variants with life-threatening cardiac arrhythmias in patients with dilated cardiomyopathy and implanted defibrillators. JAMA Network Open. 2019.

  16. •• Escobar-Lopez L, Ochoa JP, Mirelis JG, Espinosa MÁ, Navarro M, Gallego-Delgado M, et al. Association of genetic variants with outcomes in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol. 2021;78(17):1682–99. Findings from this series of patients demonstrate that the genotype underlying dilated cardiomyopathy is important in terms of prognosis. This cohort is one of the largest with available follow-up and outcome information.

    Article  CAS  Google Scholar 

  17. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, et al. Genetic variants associated with cancer therapy-induced cardiomyopathy. Circulation. 2019;140(1):31–41.

    Article  CAS  Google Scholar 

  18. Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar-Mendiguchía J, et al. Genetic etiology for alcohol-induced cardiac toxicity. J Am Coll Cardiol. 2018;71(20):2293–302.

    Article  CAS  Google Scholar 

  19. Goli R, Li J, Brandimarto J, Levine LD, Riis V, McAfee Q, et al. Genetic and phenotypic landscape of peripartum cardiomyopathy. Circulation. 2021:1852–62.

  20. Sugumar H, Prabhu S, Voskoboinik A, Kistler PM. Arrhythmia induced cardiomyopathy. J Arrhyth. 2018;34(4):376–83.

    Article  Google Scholar 

  21. Rasicci DV, Tiwari P, Desetty R, Sadler F, Sivaramakrishnan S, Craig RW, et al. Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting heads motif and super-relaxed state of myosin. Available from: https://doi.org/10.1101/2022.02.18.480995.

  22. Carrier L. Targeting the population for gene therapy with MYBPC3. J Mol Cell Cardiol. Academic Press. 2021;150:101–8.

  23. Peña-Peña ML, Monserrat L. Risk stratification in patients with nonisquemic dilated cardiomyopathy. The Role of Genetic Testing. Revista Española de Cardiología (English Edition). 2019;72(4):333–40.

  24. van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou R ben, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death?. J Mol Med. 2005;83:79–83.

  25. Ishikawa T, Mishima H, Barc J, Takahashi MP, Hirono K, Terada S, et al. Cardiac emerinopathy: a nonsyndromic nuclear envelopathy with increased risk of thromboembolic stroke due to progressive atrial standstill and left ventricular noncompaction. Circulation: Arrhyth Electrophysiol. 2020:1165–74.

  26. Guo W, Schafer S, Greaser ML, Radke MH, Liss M, Govindarajan T, et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med. 2012;18(5):766–73.

    Article  CAS  Google Scholar 

  27. van den Hoogenhof MMG, Beqqali A, Amin AS, van der Made I, Aufiero S, Khan MAF, et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling. Circulation. 2018;138(13):1330–42.

    Article  Google Scholar 

  28. Ortiz-Genga MF, Cuenca S, Dal Ferro M, Zorio E, Salgado-Aranda R, Climent V, et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol. 2016;68(22):2440–51.

    Article  CAS  Google Scholar 

  29. Domínguez F, Cuenca S, Bilińska Z, Toro R, Villard E, Barriales-Villa R, et al. Dilated cardiomyopathy due to BLC2-associated Athanogene 3 (BAG3) mutations. J Am Coll Cardiol. 2018;72(20):2471–81.

    Article  Google Scholar 

  30. van Spaendonck-Zwarts KY, van Hessem L, Jongbloed JDH, de Walle HEK, Capetanaki Y, van der Kooi AJ, et al. Desmin-related myopathy. Clin Genet. 2011;80(4):354–66.

    Article  Google Scholar 

  31. Bermúdez-Jiménez FJ, Carriel V, Brodehl A, Alaminos M, Campos A, Schirmer I, et al. Novel desmin mutation p.Glu401Asp impairs filament formation, disrupts cell membrane integrity, and causes severe arrhythmogenic left ventricular cardiomyopathy/dysplasia. Circulation. 2018;137(15):1595–610.

  32. Wahbi K, Béhin A, Charron P, Dunand M, Richard P, Meune C, et al. High cardiovascular morbidity and mortality in myofibrillar myopathies due to DES gene mutations: a 10-year longitudinal study. Neuromuscul Disord. 2012;22(3):211–8.

    Article  Google Scholar 

  33. Shirokova N, Niggli E. Cardiac phenotype of Duchenne muscular dystrophy: insights from cellular studies. J Mol Cell Cardiol. 2013;58:217–24.

    Article  CAS  Google Scholar 

  34. Peters S, Thompson BA, Perrin M, James P, Zentner D, Kalman JM, et al. Arrhythmic phenotypes are a defining feature of dilated cardiomyopathy-associated SCN5A variants: a systematic review. Circulation: Genomic and Precision Medicine. Lippincott Williams and Wilkins. 2022;15:E003432.

  35. van der Zwaag PA, van Rijsingen IAW, Asimaki A, Jongbloed JDH, van Veldhuisen DJ, Wiesfeld ACP, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14(11):1199–207.

    Article  Google Scholar 

  36. Cardiomyopathy M, Meyers DE, Haseeb F, Basha I, Koenig MK. Texas Heart Institute Journal Mitochondrial Cardiomyopathy. 2013.

  37. Agnetti A, Bitton L, Tchana B, Raymond A, Carano N. Primary carnitine deficiency dilated cardiomyopathy: 28 years follow-up. Int J Cardiol. 2013;162(2).

  38. Mirelis JG, Escobar‐Lopez L, Ochoa JP, Espinosa MÁ, Villacorta E, Navarro M, et al. Combination of late gadolinium enhancement and genotype improves prediction of prognosis in non‐ischaemic dilated cardiomyopathy. Europ J Heart Fail [Internet]. 2022. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2514.

  39. Corrado D, Perazzolo Marra M, Zorzi A, Beffagna G, Cipriani A, de Lazzari M, et al. Diagnosis of arrhythmogenic cardiomyopathy: the Padua criteria. Int J Cardiol. 2020;15(319):106–14.

    Article  Google Scholar 

  40. James CA, Bhonsale A, Tichnell C, Murray B, Russell SD, Tandri H, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol. 2013;62(14):1290–7.

    Article  Google Scholar 

  41. • Barriales-Villa R, Ochoa JP, Larrañaga-Moreira JM, Salazar-Mendiguchía J, Díez-López C, Restrepo-Córdoba MA, et al. Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry. Revista Española de Cardiología (English Edition). 2021;74(3):216–24. This work is focused on a specific genetic substrate, pathogenic variants in LMNA associated with cardiomyopathy. It is the first work that indicates that men and women can have a similar prognosis; also that certain missense variants in LMNA may have a similar and even more adverse clinical course than the set of truncation-type variants.

  42. Wahbi K, Meune C, Porcher R, Bécane HM, Lazarus A, Laforêt P, et al. Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease [Internet]. Available from: https://jamanetwork.com/.

  43. McNally EM, Mann DL, Pinto Y, Bhakta D, Tomaselli G, Nazarian S, et al. Clinical care recommendations for cardiologists treating adults with myotonic dystrophy. J Am Heart Assoc. 2020;9(4).

  44. Yeoh T, Hayward C, Benson V, Sheu A, Richmond Z, Feneley MP, et al. A randomised, placebo-controlled trial of carvedilol in early familial dilated cardiomyopathy. Heart Lung Circ. 2011;20(9):566–73.

    Article  CAS  Google Scholar 

  45. Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A, et al. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ follow-up. Am Heart J. 2007;154(3):596–602.

    Article  CAS  Google Scholar 

  46. te Rijdt WP, Hoorntje ET, de Brouwer R, Oomen A, Amin A, van der Heijden JF, et al. Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST). Neth Hear J. 2022;30(2):84–95.

    Article  Google Scholar 

  47. Muchir A, Wu W, Choi JC, Iwata S, Morrow J, Homma S, et al. Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet. 2012;21(19):4325–33.

    Article  CAS  Google Scholar 

  48. Teerlink JR, Felker GM, McMurray JJV, Solomon SD, Adams KF, Cleland JGF, et al. Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. The Lancet. 2016;388(10062):2895–903.

    Article  CAS  Google Scholar 

  49. Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, et al. Cardiac myosin activation with Omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384(2):105–16.

    Article  CAS  Google Scholar 

  50. Elangkovan N, Dickson G. Gene therapy for Duchenne Muscular Dystrophy. Vol. 8, Journal of neuromuscular diseases. NLM (Medline). 2021:S303–16.

  51. Azibani F, Brull A, Arandel L, Beuvin M, Nelson I, Jollet A, et al. Gene therapy via trans-splicing for LMNA-related congenital muscular dystrophy. Molecular Therapy - Nucleic Acids. 2018;2(10):376–86.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Scientific Department, Health in Code S.L., A Coruña, Spain

    Soledad García-Hernandez

  2. Inherited Cardiac Diseases Unit, Hospital Universitario San Cecilio, Granada, Spain

    Soledad García-Hernandez

  3. Dilemma Solutions S.L., A Coruña, Spain

    Lorenzo Monserrat Iglesias

Authors
  1. Soledad García-Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lorenzo Monserrat Iglesias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorenzo Monserrat Iglesias.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Myocardial Disease

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

García-Hernandez, S., Iglesias, L.M. Genetic Testing as a Guide for Treatment in Dilated Cardiomyopathies. Curr Cardiol Rep 24, 1537–1546 (2022). https://doi.org/10.1007/s11886-022-01772-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-022-01772-8

Keywords

Search

Navigation