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Using Genetic Testing to Guide Therapeutic Decisions in Cardiomyopathy

  • Heart Failure (J Fang, Section Editor)
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Opinion statement

Genetic analysis of human cardiomyopathy has rapidly transitioned from a strictly research endeavor to a diagnostic tool readily available to clinicians across the globe. In contemporary practice, genetic testing improves the efficiency of family evaluations and clarifies the etiology of ambiguous clinical presentations. The great promise of genetic diagnosis is to enable preventative therapies for individuals at high risk of future disease development, a strategy that is under active clinical investigation. However, in the present and future, careful interpretation of DNA sequence variation is critical, and can be ensured by referral to a specialized cardiovascular genetics clinic.

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References and Recommended Reading

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

  1. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107:2227–32.

    Article  PubMed  Google Scholar 

  2. Herman DS, Lam L, Taylor MRG, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. New Engl J Med. 2012;366:619–28. In this paper, mutations in TTN, which encodes the giant protein titin, are shown to be the most common genetic cause of dilated cardiomyopathy.

    Article  PubMed  CAS  Google Scholar 

  3. Marcus FI, Edson S, Towbin JA. Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy: A Practical Guide for Physicians. J Am Coll Cardiol. 2013.

  4. Page SP, Kounas S, Syrris P, Christiansen M, Frank-Hansen R, Andersen PS, et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet. 2012;5:156–66.

    Article  PubMed  CAS  Google Scholar 

  5. Lakdawala NK, Dellefave L, Redwood CS, Sparks E, Cirino AL, Depalma S, et al. Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy. J Am Coll Cardiol. 2010;55:320–9.

    Article  PubMed  CAS  Google Scholar 

  6. Ho CY, MacRae CA. Defining the pathogenicity of DNA sequence variation. Circ Cardiovasc Genet. 2009;2:95–7. In this paper, sequence analysis and criteria to distinguish disease causing DNA variants (mutations) from benign variation are reviewed.

    Article  PubMed  CAS  Google Scholar 

  7. Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail. 2012;18:296–303.

    Article  PubMed  Google Scholar 

  8. Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol. 2011;57:1641–9.

    Article  PubMed  CAS  Google Scholar 

  9. Hershberger RE. Cardiovascular genetic medicine: evolving concepts, rationale, and implementation. J Cardiovasc Transl Res. 2008;1:137–43.

    Article  PubMed  Google Scholar 

  10. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012;98:625–30.

    Article  PubMed  Google Scholar 

  11. Miller EM, Wang Y, Ware SM. Uptake of cardiac screening and genetic testing among hypertrophic and dilated cardiomyopathy families. J Genet Couns. 2013;22:258–67.

    Article  PubMed  Google Scholar 

  12. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. New Engl J Med. 1992;327:685–91.

  13. Colucci WS, Kolias TJ, Adams KF, Armstrong WF, Ghali JK, Gottlieb SS, et al. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial. Circulation. 2007;116:49–56.

    Article  PubMed  CAS  Google Scholar 

  14. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:2761–96.

    Article  PubMed  Google Scholar 

  15. Ashley EA, Hershberger RE, Caleshu C, Ellinor PT, Garcia JGN, Herrington DM, et al. Genetics and cardiovascular disease: a policy statement from the American Heart Association. Circulation. 2012;126:142–57.

    Article  PubMed  Google Scholar 

  16. Christiaans I, Van Langen IM, Birnie E, Bonsel GJ, Wilde AAM, Smets EMA. Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study. Am J Med Genet. 2009;149A:602–12. Part A.

    Article  PubMed  Google Scholar 

  17. Ho CY. Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy. Circulation. 2010;122:2430–40; discussion 2440. The current limitations of utilizing genetic data to manage patients with hypertrophic cardiomyopathy are balanced against its future potential to fundamentally alter the treatment of this disease.

    Google Scholar 

  18. Lakdawala NK, Givertz MM. Dilated cardiomyopathy with conduction disease and arrhythmia. Circulation. 2010;122:527–34.

    Article  PubMed  Google Scholar 

  19. Arad M, Maron BJ, Gorham JM, Johnson WH, Saul JP, Perez-Atayde AR, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. New Engl J Med. 2005;352:362–72.

    Article  PubMed  CAS  Google Scholar 

  20. Rao DA, Lakdawala NK, Miller AL, Loscalzo J. Clinical problem-solving. In the thick of it. New Engl J Med. 2013;368:1732–8.

    Article  PubMed  CAS  Google Scholar 

  21. Gambarin FI, Disabella E, Narula J, Diegoli M, Grasso M, Serio A, et al. When should cardiologists suspect Anderson-Fabry disease? Am J Cardiol. 2010;106:1492–9.

    Article  PubMed  Google Scholar 

  22. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. 2009;301:1253–9.

    Article  PubMed  CAS  Google Scholar 

  23. Brezina PR, Brezina DS, Kearns WG. Preimplantation genetic testing. BMJ (Clinical research ed). 2012;345:e5908.

    Article  Google Scholar 

  24. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. New Engl J Med. 1992;326:1108–14.

    Article  PubMed  CAS  Google Scholar 

  25. Fananapazir L, Epstein ND. Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations. Circulation. 1994;89:22–32.

    Article  PubMed  CAS  Google Scholar 

  26. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation. 2010;122:2441–9. discussion 2450.

    Article  PubMed  Google Scholar 

  27. Sen-Chowdhry S, Syrris P, Prasad SK, Hughes SE, Merrifield R, Ward D, et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol. 2008;52:2175–87.

    Article  PubMed  Google Scholar 

  28. Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2008;83:630–8.

    PubMed  CAS  Google Scholar 

  29. Van Rijsingen IAW, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, Van der Kooi AJ, et al. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol. 2012;59:493–500.

    Article  PubMed  Google Scholar 

  30. Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease: a marker of disease severity? Circ Cardiovasc Genet. 2009;2:182–90.

    Article  PubMed  CAS  Google Scholar 

  31. Maron BJ, Ho CY. Hypertrophic cardiomyopathy without hypertrophy: an emerging pre-clinical subgroup composed of genetically affected family members. JACC Cardiovasc Imaging. 2009;2:65–8.

    Article  PubMed  Google Scholar 

  32. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002;105:2992–7.

    Article  PubMed  Google Scholar 

  33. Lakdawala NK, Thune JJ, Maron BJ, Cirino AL, Havndrup O, Bundgaard H, et al. Electrocardiographic features of sarcomere mutation carriers with and without clinically overt hypertrophic cardiomyopathy. Am J Cardiol. 2011;108:1606–13.

    Article  PubMed  Google Scholar 

  34. Ho CY, Abbasi SA, Neilan TG, Shah R V, Chen Y, Heydari B, et al. T1 Measurements Identify Extracellular Volume Expansion in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy. Circ Cardiovasc Imaging. 2013;6:415–2.

    Google Scholar 

  35. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. New Engl J Med. 2010;363:552–63.

    Article  PubMed  CAS  Google Scholar 

  36. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol. 2003;41:1776–82.

    Article  PubMed  CAS  Google Scholar 

  37. Lakdawala NK, Thune JJ, Colan SD, Cirino AL, Farrohi F, Rivero J, et al. Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy. Circ Cardiovasc Genet. 2012;5:503–10.

    Article  PubMed  Google Scholar 

  38. Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, et al. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Investig. 2002;109:1013–20.

    PubMed  CAS  Google Scholar 

  39. Suckau L, Fechner H, Chemaly E, Krohn S, Hadri L, Kockskämper J, et al. Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation. 2009;119:1241–52.

    Article  PubMed  CAS  Google Scholar 

  40. Oh Y, Wei H, Ma D, Sun X, Liew R. Clinical applications of patient-specific induced pluripotent stem cells in cardiovascular medicine. Heart. 2012;98:443–9.

    Article  PubMed  CAS  Google Scholar 

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Neal K Lakdawala reported no potential conflicts of interest relevant to this article.

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

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Authors and Affiliations

  1. Brigham and Women’s Hospital, Division of Cardiovascular Medicine, VA Boston Health Care, Harvard Medical School, Boston, MA. 75 Francis Street, Boston, MA, 02115, USA

    Neal K. Lakdawala MD

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  1. Neal K. Lakdawala MD
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Correspondence to Neal K. Lakdawala MD.

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Lakdawala, N.K. Using Genetic Testing to Guide Therapeutic Decisions in Cardiomyopathy. Curr Treat Options Cardio Med 15, 387–396 (2013). https://doi.org/10.1007/s11936-013-0252-7

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